N-Substituted phenylalkylamines and their use as therapeutic agents

Abstract

N-Substituted phenylalkylamines, methods for their preparation, and methods of using such compounds, for example as receptor probes, as regulators of neurotransmission, and as therapeutic agents, for example as CNS agents, are provided. Pharmaceutical compositions for treating specific disorders, for example disorders associated with serotonergic neurotransmission, mental health disorders, and ion channel-mediated conditions, for example seizure disorders, and methods of using the same are also provided.

Description

Technical Field

[0001] Cross - reference to related applications Claims the priority based on PCT Article 8(1) and Rule 4.10 to U.S. Patent Application No. 63 / 355,632, filed on June 26, 2022, which is incorporated by reference in its entirety for all purposes as if fully set forth herein.

[0002] In some aspects, the present disclosure relates to N - substituted phenylalkylamine compounds. In some aspects, the invention further relates to methods of synthesizing the compounds, compositions containing the compounds, and methods of using such compounds, including their administration to a subject. In some aspects, useful features of the compounds include neuromodulatory activity.

Background Art

[0003] Tryptamine-class psychedelic compounds such as psilocybin and DMT are emerging as promising therapeutic candidates for treating a number of psychiatric conditions, including depressive disorders, substance use disorders, and anxiety-related disorders (Vollenweider and Preller, Nat Rev Neurosci, 2020;21(11):611-624; D’Souza et al., Neuropsychopharmacol., 2022;47(10):1854-1862). Apart from their prominent subjective effects on consciousness, there is growing interest in their physiological effects and potential applications in the treatment of physical and neurological disorders. Furthermore, although much progress has been made in recent years towards understanding the structure-activity relationships underlying the effects of classical psychedelic drugs, many unresolved questions remain regarding the effectiveness and potential risks of these compounds for treating complex diseases that may lack effective treatments, such as mood disorders (e.g., depressive disorders, bipolar disorder) and psychotic disorders (e.g., schizophrenia). Accordingly, there remains a continuing unmet need for new alternative treatments, particularly those that improve upon existing classical psychedelic drugs by minimizing side effects, increasing access, optimizing effectiveness, and even invoking new mechanisms of action.

[0004] Compounds, compositions, methods, uses, and pharmaceutical kits are provided herein that meet these and other needs and have advantages and improvements as will become readily apparent through the following disclosure.

[0005] Incorporation by reference Each patent, publication, and non-patent document cited in this application is hereby incorporated by reference in its entirety as if each were individually incorporated by reference and as if each were fully described herein. However, when such reference is made, it is for the general purpose of providing a context for discussing the disclosed features and should not be construed as an admission that the document or underlying information is part of the prior art or common general knowledge in any jurisdiction, unless specifically stated otherwise.

SUMMARY OF THE INVENTION

[0006] The following presents a simplified summary of some embodiments of the present invention to provide a basic understanding of the present invention. This summary is not an extensive overview of the present invention. It is not intended to identify key or essential elements of the present invention or to delineate the scope of the present invention. Its sole purpose is to present some embodiments of the present invention in a simplified form as a prelude to the more detailed description that follows.

[0007] In a first aspect, formula (II):

CHEMICAL

[0008] In some embodiments, both R and R2 are -OCH3.

[0009] In some embodiments, R3 is hydrogen, -CH3 or -CH2CH3. In some embodiments, R3 is hydrogen or -CH3. In some embodiments, R3 is -CH3 or -CH2CH3. In some embodiments, R3 is hydrogen. In some embodiments, R3 is -CH3. In some embodiments, R3 is -CH2CH3.

[0010] In some embodiments, R1 is F, Cl, Br, or I. In some embodiments, R1 is Br. In some embodiments, R1 is C1-C8 alkyl. In some embodiments, R1 is -CH3 or -CH2CH3. In some embodiments, R1 is C1-C8 thioalkyl. In some embodiments, R1 is -SCH3. In some embodiments, R1 is unsubstituted phenyl. In some embodiments, R1 is phenyl substituted by azide or C1-C8 alkoxy.

[0011] In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NH.

[0012] In some embodiments, the sum of m + n is from 8 to 12. In some embodiments, the sum of m + n is from 9 to 11. In some embodiments, the sum of m + n is 10. In some embodiments, m is 6 and n is 4.

[0013] In another aspect, there is provided a compound selected from Table 4 or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound is [Table 1] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound is [Chemical Formula] or a pharmaceutically acceptable salt thereof.

[0016] There is also provided a pharmaceutical composition comprising a therapeutically effective amount of the compound of the foregoing embodiments or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient.

[0017] In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injection, subcutaneous, intravenous, or transdermal administration.

[0018] In some embodiments, the composition is in unit dosage form. In some embodiments, the unit dosage form contains the compound or a pharmaceutically acceptable salt thereof in a total amount of about 1 to about 500 mg, about 2.5 to about 250 mg, or about 5 to about 125 mg. In some embodiments, the unit dosage form is an immediate release formulation, a controlled release formulation, a sustained release formulation, a slow release formulation, or a modified release formulation.

[0019] In some embodiments, the composition further comprises a therapeutically effective amount of a further active compound or a pharmaceutically acceptable salt thereof. In some embodiments, the further active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathic and anti-nociceptive agents, anti-migraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anti-cancer agents, anti-emetics, appetite stimulants, anti-ulcer agents, antihistamines, antihypertensives, anti-spasmodics, anti-epileptics, bronchodilators, neuroprotective agents, nootropics, empathogens, psychedelic drugs, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, and vitamins, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the additional active compound or a pharmaceutically acceptable salt thereof acts to increase the therapeutic effect, provide an additional therapeutic effect, reduce undesirable effects, increase stability or shelf life, improve bioavailability, induce a synergistic effect, or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anti-anxiety, anti-depressant, anti-psychotic, anti-PTSD, dissociative-promoting, immunostimulatory, anti-cancer, anti-emetic, appetite-promoting, anti-ulcer, anti-histamine, antihypertensive, anti-spasmodic, anti-epileptic, bronchodilatory, neuroprotective, nootropic, empathogenic, psychedelic, sedative, or stimulatory.

[0021] In another aspect, there is provided a compound of any of the foregoing embodiments or a pharmaceutically acceptable salt thereof for use in the treatment of a medical condition.

[0022] In another aspect, there is provided a compound of any of the foregoing embodiments or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a medical condition.

[0023] In another aspect, there is provided a method of modulating neurotransmission in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of any of the foregoing embodiments or a pharmaceutically acceptable salt thereof.

[0024] There is also provided a method of treating a medical condition in a mammal in need of such treatment, the method comprising administering a compound of any of the foregoing embodiments or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the medical condition is a disorder associated with dysregulation or insufficient function of neurotransmission. In some embodiments, the disorder associated with dysregulation or insufficient function of neurotransmission is a disorder of monoaminergic neurotransmission. In some embodiments, the disorder associated with dysregulation or insufficient function of neurotransmission is a disorder of serotonergic neurotransmission.

[0026] In some embodiments, the medical condition is a mental health disorder. In some embodiments, the mental health disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, substance-induced psychotic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, post-traumatic stress disorder (PTSD), adjustment disorder, mood disorder, depression, atypical depression, postpartum depression, melancholic depression, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, mood swings, anxiety disorder, phobic disorder, eating disorder, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance use disorder, substance-induced mood disorder, mood disorder related to another health condition, disruptive behavior disorder, feeding disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, and dissociative disorder.

[0027] In some embodiments, the medical condition is a seizure disorder. In some embodiments, the seizure disorder is epilepsy.

[0028] In some embodiments, the medical condition is a disorder associated with dysregulation or insufficient function of voltage-dependent ion channels. In some embodiments, the voltage-dependent ion channel is a voltage-dependent sodium channel. In some embodiments, the compound inhibits the activity of the voltage-dependent sodium channel.

[0029] In some embodiments, the mammal has a genetic variation related to drug metabolism, including a genetic variation related to the CYP2D6 or CYP3A4 enzyme, or is related to a mental health disorder, a psychological trauma or stress-related disorder, depression or anxiety disorder, and includes a genetic variation of mGluR5 or FKBP5, or has a genetic variation related to a membrane transporter such as SERT, DAT, NET or VMAT.

[0030] In some embodiments, the mammal has an altered epigenetic control of a gene, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor, whose expression is related to mental health status or sensitivity to mental health treatment.

[0031] In some embodiments, the mammal is a human.

[0032] Also provided is a method for reducing symptoms of a mental health disorder in a human, the method comprising identifying a human in need of such reduction and administering to the human a compound of any of the foregoing embodiments or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any of the foregoing embodiments.

[0033] Also provided is a method for improving mental health or function in a human, the method comprising identifying a human in need of such improvement and administering to the human a compound of any of the foregoing embodiments or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any of the foregoing embodiments.

[0034] The foregoing is a broad summary and overview of certain relevant features of the present disclosure in order that the following detailed description of the invention may be better understood, and thus that the contribution of the invention to the art may be more fully appreciated. Accordingly, this summary should be regarded as only a brief and general overview of some of the purposes and embodiments disclosed herein, provided solely for the benefit and convenience of the reader, and not intended to limit in any way the scope of the claims or the equivalents thereof. Further features of the invention are described below. It should be understood by those skilled in the art that all of the specific compositions and methods disclosed are merely exemplary and can be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purpose. Such equivalent compositions and methods are also understood to be within the scope and spirit of the present disclosure as set forth in the claims.

[0035] The headings within this document are utilized solely to facilitate review by the reader. They should not be construed as limiting the invention in any way.

[0036] To further clarify various aspects of the present invention, a more detailed description of the invention is provided by reference to specific exemplary embodiments of the invention shown in the drawings. It will be understood and recognized that the drawings show only exemplary embodiments of the invention and should not be regarded as limiting its scope. They are provided merely as illustrative examples of some embodiments of the invention. Accordingly, specific aspects of the invention are further described and explained below with reference to the following accompanying drawings, but are merely examples.

Brief Description of the Drawings

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BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Although various aspects and features of the specific embodiments have been summarized above, the following detailed description further shows several exemplary embodiments in order to enable those skilled in the art to practice such embodiments and to make and use the full scope of the claimed invention. The examples described are provided for purposes of illustration and are not intended to limit the scope of the invention or its use to those specifically described, nor to all embodiments and their formulations. It will be understood that many modifications, substitutions, changes, and variations in the examples, embodiments, uses, and details of the invention shown herein can be made by those skilled in the art without departing from the spirit of the invention or the scope of the claimed invention.

[0058] A. General Definitions and Terms As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an active agent” includes reference to combinations of two or more active agents, and reference to “an excipient” includes reference to combinations of two or more excipients. The term “one or more” may be used, and its absence (or substitution by the singular) does not mean only the singular, but rather emphasizes only the possibility of plural agents or components in a particular embodiment.

[0059] The terms "comprising", "such as", and "having" are intended to be inclusive and not exclusive (i.e., other elements may be present in addition to the recited elements). Thus, as used herein, the term "comprising" means the phrase "comprising but not limited to" and is used interchangeably therewith. The term "or" as used herein is used to mean the term "and / or" and is used interchangeably therewith, unless the context clearly indicates otherwise.

[0060] Unless otherwise specified, all numbers expressing amounts of ingredients, properties such as concentrations, reaction conditions, etc., used to describe and claim particular embodiments of the invention are to be understood as being modified in some instances by the term "about". Accordingly, in embodiments, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, "about" refers to plus or minus 5 percent (±5%) of the recited units of measurement. In embodiments, the term "from" when used in the context of a numerical range includes both boundary numbers within the range. For example, the phrase "from 1 to 10" includes the numbers 1 and 10. The term "substantially" when applied to modify a feature or limitation herein is read with appropriate certainty in the context of the invention and in light of the knowledge in the art, using, for example, standards recognized in the art to measure the meaning of "substantially" as a term of degree or by checking ranges as would be understood by a person of ordinary skill in the art to provide appropriate certainty.

[0061] In some embodiments (equally, as an abbreviated expression, "in embodiments"), numerical parameters should be construed in light of the reported number of significant digits and by applying ordinary rounding techniques. Although the numerical ranges and parameters that indicate the broad scope of some embodiments of the present invention are approximations, the numerical values shown in the specific examples are reported as accurately as practicable. The numerical values presented in some embodiments may include certain errors that necessarily result from the standard deviation found in each of the test measurements.

[0062] A comprehensive list of the abbreviations used by organic chemists, who are those skilled in the art, is shown in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled "Standard List of Abbreviations"; the list as of the filing date of this application is incorporated herein by reference as if fully set forth herein.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs, who may simply be referred to herein by the shorthand "skilled artisan". Further definitions that may assist the reader in understanding the disclosed embodiments are as follows; however, such definitions are not intended to limit the scope of the present invention and should be construed and understood appropriately by reference to the complete specification (as well as any plain meaning known to those skilled in the relevant art) in view of the language used in the appended claims. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0064] Generally, the nomenclature used herein and the procedures performed are those known in the fields related to one or more aspects of the present invention, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or pharmaceutical chemistry, well-known and commonly used in such fields. Standard techniques and procedures are generally performed in accordance with conventional methods in the art.

[0065] "Alkyl" is understood to include straight-chain or branched radicals having any degree or level of saturation, i.e., groups having only single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having a mixture of single, double, and triple carbon-carbon bonds. When a particular level of saturation is intended, the expressions "alkanyl", "alkenyl", and "alkynyl" can also be used. Preferably, the alkyl group contains from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, and most preferably from 1 to 3 carbon atoms. For any alkyl, the alkyl may optionally be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2 and -SONH2.

[0066] "Alkanil" refers to a saturated branched, straight-chain or cyclic alkyl radical derived by removing one hydrogen atom from a single carbon atom of the parent alkane. Typical alkanil groups include methanyl; ethanil; propanil, such as propane-1-yl, propane-2-yl (isopropyl), cyclopropane-1-yl; butanil, such as butane-1-yl, butane-2-yl (sec-butyl), 2-methyl-propane-1-yl (isobutyl), 2-methyl-propane-2-yl (t-butyl) and cyclobutane-1-yl, etc.

[0067] "Alkenyl" refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by removing one hydrogen atom from a single carbon atom of the parent alkene. The group can be in either the cis or trans conformation with respect to the double bond(s). Typical alkenyl groups include ethenyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl and cycloprop-2-en-1-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, but-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl and cyclobut-1,3-dien-1-yl, etc.

[0068] "Alkynyl" refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom of the parent alkyne. Typical alkynyl groups include ethynyl; propynyl, such as prop-1-yn-1-yl and prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl and but-3-yn-1-yl, etc.

[0069] "Aryl" refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc. Preferably, the aryl group contains 6 to 20 or more preferably 6 to 12 carbon atoms.

[0070] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the indicated number of atoms. Cycloalkyl can contain any number of carbons such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Examples of monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Examples of bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene and adamantane. When the cycloalkyl is monocyclic C 3-8 When the cycloalkyl is a cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When the cycloalkyl is monocyclic C 3-6 When the cycloalkyl is a cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted or unsubstituted.

[0071] "Cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring. However, when two or more double bonds are present, they cannot form a completely delocalized π - electron system across all rings (otherwise, the group would be "aryl" as defined herein). When composed of two or more rings, the rings can be connected to each other in a fused manner. Cycloalkenyl can contain any number of carbon atoms such as 3 - 6 carbon atoms, 4 - 6 carbon atoms, 5 - 6 carbon atoms, 3 - 8 carbon atoms, 4 - 8 carbon atoms, 5 - 8 carbon atoms, 6 - 8 carbon atoms, 7 - 8 carbon atoms, 3 - 9 carbon atoms, 4 - 9 carbon atoms, 5 - 9 carbon atoms, 6 - 9 carbon atoms, 7 - 9 carbon atoms, 8 - 9 carbon atoms, 3 - 10 carbon atoms, 4 - 10 carbon atoms, 5 - 10 carbon atoms, 6 - 10 carbon atoms, 7 - 10 carbon atoms, 8 - 10 carbon atoms, 9 - 10 carbon atoms, 3 - 11 carbon atoms, 4 - 11 carbon atoms, 5 - 11 carbon atoms, 6 - 11 carbon atoms, 7 - 11 carbon atoms, 8 - 11 carbon atoms, 9 - 11 carbon atoms, 10 - 11 carbon atoms, 3 - 12 carbon atoms, 4 - 12 carbon atoms, 5 - 12 carbon atoms, 6 - 12 carbon atoms, 7 - 12 carbon atoms, 8 - 12 carbon atoms, 9 - 12 carbon atoms, 10 - 12 carbon atoms, and 11 - 12 carbon atoms. Representative cycloalkenyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3 - and 1,4 - isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3 -, 1,4 - and 1,5 - isomers), norbornene and norbornadiene. The cycloalkenyl group may be unsubstituted or substituted.

[0072] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0073] "Heterocycloalkyl" or "heterocyclyl" refers to cycloalkyl as defined above having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Heterocycloalkyl includes bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. The heteroatoms can also be oxidized, such as -S(O)- and -S(O)2-, but are not limited thereto. The heterocycloalkyl group can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms, such as 1, 2, 3 or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4, can be included in the heterocycloalkyl group. Examples of heterocycloalkyl groups include aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane or dithiane. The heterocycloalkyl group can also condense with an aromatic or non-aromatic ring system to form members including, but not limited to, indoline. The heterocycloalkyl group can be unsubstituted or substituted. For example, the heterocycloalkyl group can be substituted, inter alia, with C1-6 alkyl or oxo (=O).

[0074] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, wherein the alkyl component connects the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that it is at least a divalent alkylene for connecting to the heterocycloalkyl component and the point of attachment. The alkyl component can contain any number of carbons such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some cases, the alkyl component may not be present. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group can be substituted or unsubstituted.

[0075] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, with 1 to 5 of the ring atoms being heteroatoms such as N, O, or S. The heteroaryl group can contain any number of ring atoms, such as 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5, can be included in the heteroaryl group. The heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl group can also form members including, but not limited to, those condensed to an aromatic ring system such as a phenyl ring, such as benzopyrrole, for example indole and isoindole, benzopyridine, for example quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine, for example phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds such as bipyridine. The heteroaryl group can be substituted or unsubstituted.

[0076] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene for bonding to the heteroaryl component and the point of attachment. The alkyl component can contain any number of carbons such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some cases, the alkyl component may not be present. The heteroaryl component is as defined above. The alkyl-heteroaryl group can be substituted or unsubstituted.

[0077] "Alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. A non-limiting list of alkoxys is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzyloxy. The alkoxy can be substituted or unsubstituted.

[0078] "Acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl bonded via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl and acrylyl. The acyl can be substituted or unsubstituted.

[0079] "Aryloxy" refers to an aryl moiety as defined herein that is bonded to an oxygen atom, where the oxygen atom serves as a point of attachment to the remainder of the molecule. Aryloxy can be either substituted or unsubstituted. Exemplary aryloxy groups include phenoxy, tolyloxy (including p - tolyloxy, m - tolyloxy, and o - tolyloxy), ethylphenyloxy (including p - ethylphenyloxy, m - ethylphenyloxy, and o - ethylphenyloxy), naphthyloxy, and the like.

[0080] "Alkylamino" refers to groups such as N - alkylamino (i.e., R - NHR') and N,N - dialkylamino (i.e., R - NR'R") in which the amino group is independently substituted with one alkyl radical (i.e., R') or two alkyl radicals (i.e., R' and R"), where R represents an alkyl as defined herein. Non - limiting examples of alkylamino groups include mono - or dialkylamines such as N - methylamino, N - ethylamino, N,N - dimethylamino, N,N - diethylamino. Alkylamino may be either unsubstituted or substituted.

[0081] "Alkylthio" or "thioalkyl" refers to the formula - SR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl as defined herein. In some embodiments where R is aryl, the - SR moiety is called "thioaryl". A non - limiting list of alkylthio or thioalkyl includes methylthio, ethylthio, n - propylthio, isopropylthio, n - butylthio, iso - butylthio, sec - butylthio, phenylthio, and benzylthio. Alkylthio or thioalkyl can be either substituted or unsubstituted.

[0082] "Aryl amide" refers to an aryl moiety as defined herein attached to an amide moiety, and the amide moiety serves as a point of attachment to the remainder of the molecule. In some embodiments, the aryl amide has the formula Ar-C(=O)NH-* or Ar-NH-C(=O)-*, where Ar is an aryl as defined herein and * represents the point of attachment to the remainder of the molecule. The aryl amide can be substituted or unsubstituted.

[0083] "Alkyl amide" refers to an alkyl moiety as defined herein attached to an amide moiety, and the amide moiety serves as a point of attachment to the remainder of the molecule. In some embodiments, the alkyl amide has the formula Ak-C(=O)NH-* or Ak-NH-C(=O)-*, where Ak is an alkyl as defined herein and * represents the point of attachment to the remainder of the molecule. The alkyl amide can be substituted or unsubstituted.

[0084] "Haloalkyl" is understood to include any alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen (e.g., fluorine, chlorine, bromine or iodine). When an alkyl group is substituted with two or more halogens, it can be referred to using a prefix corresponding to the number of halogen substitutions. For example, dihaloalkyl refers to an alkyl substituted with two halo groups, which may be the same halogen but need not necessarily be the same halogen. Examples of haloalkyl groups include difluoromethyl (-CHF2), bromofluoromethyl (-CHBrF), trifluoromethyl (-CF3) and 2-fluoroethyl (-CH2CH2F). Further examples of haloalkyl groups include -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(CH3)(CF3), -CH(CH3)(CHF2) and -CH(CH3)(CH2F).

[0085] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. Hydroxyalkyl may be substituted or unsubstituted.

[0086] "Haloalkoxy" refers to an -O-alkyl group in which one or more hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). The halogen may be the same or different in each case. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoro-methoxy and 2-fluoroisobutoxy. Haloalkoxy may be substituted or unsubstituted.

[0087] "Sulfenyl" refers to an -SR group where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. Sulfenyl may be substituted or unsubstituted.

[0088] "Sulfinyl" refers to an -S(=O)-R group where R can be the same as defined for sulfenyl. Sulfinyl may be substituted or unsubstituted.

[0089] "Sulfonyl" refers to an -SO2R group where R can be the same as defined for sulfenyl. "Alkylsulfonyl" specifically refers to an -SO2R group where R is alkyl as defined herein. Sulfonyl (or alkylsulfonyl) may be substituted or unsubstituted.

[0090] "Carboxy" refers to an -RC(=O)O- group where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. Carboxy can be substituted or unsubstituted.

[0091] "Ester" and "C-carboxy" refer to a -C(=O)OR group where R can be the same as defined for O-carboxy. "Alkyl ester" refers to a -C(=O)OR group where R is alkyl as defined herein. The ester group and the C-carboxy group may be substituted or unsubstituted.

[0092] "Thiocarbonyl" refers to a -C(=S)R group where R can be the same as defined for O-carboxy. Thiocarbonyl can be substituted or unsubstituted.

[0093] "Trihalomethanesulfonyl" refers to an X3CSO2- group where each X is halogen.

[0094] "Trihalomethanesulfonamide" refers to an X3CS(O)2N(R A )- group, wherein each X is halogen and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein.

[0095] "S-sulfonamide" refers to a -SO2N(R A R B ) group, wherein R A and R B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. S-sulfonamide can be substituted or unsubstituted.

[0096] "N-sulfonamide" refers to an RSO2N(R A )- group, wherein R and R Amay independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. The N-sulfonamide may be substituted or unsubstituted.

[0097] "Carbamoyl" includes O-carbamoyl and N-carbamoyl groups. "O-carbamoyl" refers to an -OC(=O)N(R A R B ) group, where R A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. O-carbamoyl may be substituted or unsubstituted. "N-carbamoyl" refers to an ROC(=O)N(R A )- group, where R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. N-carbamoyl may be substituted or unsubstituted.

[0098] "O-thiocarbamyl" refers to an -OC(=S)-N(R A R B ) group, where R A and R B may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. O-thiocarbamyl may be substituted or unsubstituted.

[0099] "N-thiocarbamyl" refers to an ROC(=S)N(R A )- group, where R and R A may independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. N-thiocarbamyl may be substituted or unsubstituted.

[0100] The "C-amide" group refers to a -C(=O)N(R A R B ) group, where R A and R B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. These may be optionally substituted or unsubstituted.

[0101] "N-amide" refers to an RC(=O)N(R A )- group, where R and R A are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl as defined herein. N-amide may be substituted or unsubstituted.

[0102] Unless otherwise specified, "optionally substituted" means that the group can be unsubstituted or substituted by one or more of the substituents listed for that group. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the substituent(s) can be selected from one or more of the indicated substituents. When multiple substituents are present, they can be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. When no substituent is indicated for an "optionally substituted" or "substituted" group, the indicated "optionally substituted" or "substituted" group can be substituted by one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azide, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, amino, mono-substituted amino group, di-substituted amino group, and tri-substituted amino group.

[0103] Additional definitions and abbreviations are provided elsewhere in this specification.

[0104] B. Compounds Psychedelic drugs are a unique class of psychotropic drugs defined by their ability to change thinking, feelings, and perception (Masters and Houston, The Varieties of Psychedelic Experience., Dell Publishing Co., Inc., 1966; Nichols, Pharmacol Rev., 2016; 68(2):264-355). The major chemotypes of the psychedelic class include phenylalkylamines, tryptamines, and lysergamides (Nichols, Pharmacol Rev., 2016; 68(2):264-355). The typical psychoactive effects of psychedelic phenylalkylamines, such as 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine (2C-B) (Shulgin and Carter, Psychopharmacol Commun 1, 1975.;93-98), on consciousness are mediated mainly by the activation of 5-HT 2A subtypes of serotonin (5-HT) receptors (Glennon et al., Life Sci., 1984; 35(25):2505-2511; Titeler et al., Psychopharmacology(Berl), 1988; 94(2):213-216; Vollenweider et al., Neuroreport, 1998; 9(17):3897-3902). The activation of 5-HT 2A receptors is also thought to be important for the psychoactivity of lysergamides such as lysergic acid diethylamide (LSD), as well as tryptamines such as N,N-dimethyltryptamine (DMT) and psilocin.

[0105] 5-HT 2AThe receptor belongs to the superfamily of G protein-coupled receptors that contain seven transmembrane domains (TMDs), like the β2-adrenergic receptor. When a phenethyloxyhexyl side chain is added to the β2 agonist salbutamol, salmeterol is obtained, which is a β2 agonist with improved efficacy and duration of action in the treatment of bronchoconstriction associated with asthma and chronic obstructive pulmonary disease (COPD) (Johnson, Med Res Rev., 1995; 15(3):225-257). The extended length dimension (25 Å) of the salmeterol molecule compared to the salbutamol molecule (11 Å) allows the side chain of salmeterol to bind to an accessory binding region within the β2 receptor, called the exosite, which is different from the agonist binding domain (Johnson, Med Res Rev., 1995; 15(3):225-257; Masureel et al., Nat Chem Biol., 2018; 14(11):1059-1066).

[0106] Evidence from site-directed mutagenesis, chimeric β1 / β2 receptors, photoaffinity labeling, X-ray crystallography, and computer modeling of the β2 receptor localizes the exosite within TMD4, 6, and 7 of the β2 receptor and extracellular loops (ECL) 2 and 3. (Green et al., J Biol Chem., 1996; 271(39):24029-24035; Isogaya et al., Mol Pharmacol., 1998; 54(4):616-622; Johnson, Med Res Rev., 1995; 15(3):225-257; Masureel et al., Nat Chem Biol., 2018; 14(11):1059-1066; Rong 1999). The X-ray crystal structure of salmeterol bound to the β2 receptor shows that the aryloxyalkyl tail occupies a cleft formed by residues from extracellular loops ECL2, ECL3, and the extracellular termini of TMD6 and TMD7 (Masureel et al., Nat Chem Biol., 2018; 14(11):1059-1066).

[0107] Using the UniProt Align alignment routine (https: / / www.uniprot.org / ), the amino acid sequence alignment between the human β2 receptor and the human 5-HT 2A After the amino acid sequence alignment with the receptor, 5 HT 2A The amino acid sequences in the three TMDs of the 5-HT receptor show high sequence homology (70 - 94%) with the three TMDs including the β2 receptor exosite, but it was observed that ECL 2 and 3 show lower homology (<50% conserved). Based on these sequence homologies, similar to the β2 receptor, the 5-HT 2A Receptor was hypothesized to contain an exosite that could engage the extended N-linked side chain of the modified 5-HT 2A agonist.

[0108] In a first aspect, substituted phenylalkylamine compounds having an N-linked side chain are provided herein. Phenylalkylamines share a chemical structure similar to amphetamines, catecholamines, synthetic cathinones, and other substances, and are stimulant, entactogenic / empathogenic, and / or hallucinogenic / psychedelic substances (Nelson et al., Emerg Med Clin North Am., 2014;32(1):1 - 28). Phenylalkylamines include both natural and synthetic substances, including classical phenethylamines such as MDMA, MDEA, and MBDB, as well as mescaline-derived compounds such as TMA, DOM, DOET, DOI, and DOC. More recently described phenylalkylamines include bromodragonfly, benzofuran, N-benzyl-substituted phenylalkylamine substances, and "2C series" such as 2C-I, 2C-E, 2C-B, and other "2C-X" compounds (Schifano et al., World Psychiatry, 2015;14(1):15 - 26; Shulgin & Shulgin, PIHKAL: A Chemical Love Story, Transform Press, Berkeley, CA, 1991).

[0109] In some embodiments, the term "phenylalkylamine" refers to a phenylalkylamine having the structure of formula (A), wherein R N1 , R N2 , R α , R β , and R 2 ~R 6 each is as defined herein and as understood in the art:

Chemical formula

[0110] In some embodiments of formula (A), each of R N1 , R N2 , R α , R β , and R 2 ~R 6 is independently hydrogen, halogen, C1-C5 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl (optionally a ring closed by nitrogen in the case of RN), C3-C8 cycloalkenyl (optionally a ring closed by nitrogen in the case of RN), aryl, or heterocyclyl; R3 and R4 together can form dioxolane (similar to MDMA), furan, tetrahydrofuran, thiophene, pyrrole, pyridine, pyrrolidine, ethylene oxide, ethyleneimine, trimethylene oxide, pyran, piperidine, imidazole, thiazole, dioxane, morpholine, pyrimidine, or can generate a benzene heterocycle, and all of these can be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2 and -SONH.

[0111] In some embodiments of formula (A), R N1 , R N2 , R α , R β , and R 2~6 are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In some embodiments, R 3 and R 4 together form an optionally substituted heterocyclyl such as dioxol (similar to MDMA), furan, tetrahydrofuran, thiophene, pyrrole, pyridine, pyrrolidine, ethylene oxide, ethyleneimine, trimethylene oxide, pyran, piperidine, imidazole, thiazole, dioxane, morpholine or pyrimidine. In some embodiments, R 3 and R 4 together form an optionally substituted aryl such as phenyl. In some embodiments, phenethylamine contains a quaternary ammonium cation in which R N1 , R N2 , and a further R N3 are each independently an alkyl group or an aryl group and have all the other substituents as described above. In an embodiment, phenethylamine is a quaternary salt in which a further R N1 and R N2 are attached to the nitrogen to which R N3 is connected; R N3 is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0112] In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (A) having an N-linked side chain. In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (A), where one of RN1 and RN2 is a side chain as described in the embodiments herein, and the other of RN1 and RN2 is as defined above.

[0113] In some embodiments, the term "phenylalkylamine" refers to 2C phenethylamine. The 2C series of phenethylamines, which are known and referred to herein as "2C" or "2C-X" compounds, are ring-substituted phenethylamines that contain methoxy groups at the 2- and 5-positions of the benzene ring and often a lipophilic substituent at the 4-position. In some embodiments, the 2C phenethylamine is a phenylalkylamine having the structure of formula (B):

Chemical formula

[0114] In some embodiments of formula (B), R’ and R” are independently selected from hydrogen, N, NO2, Cl, Br, F, I, CH3, CH3O-, CH3CH2O-, CH3CH2CH2O-, CF3O-, CF3CH2O-, CF3CH2CH2O-, CH3CH2-, CH3CH2CH2-, CH3S-, CH3CH2S-, (CH3)2CHS-, CH3CH2CH2S-, CH3CH2CH2CH2S-, (CH3)3CS-, CF3CH2-, CF3CH2CH2-, CF3S-, CF3CH2S-, CF3CH2CH2S-, FCH2CH2S-, or (CH2) 1-6 -(CH2) 0-5 - and are independently selected, and (CH2) 1-6 is either a fused (when CH2=0) or non-fused 3-, 4-, 5- or 6-membered ring system and may include a bridged or aromatic ring system. In some embodiments, R’ is hydrogen and R” is as defined above. In some embodiments, both R’ and R” are hydrogen.

[0115] In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (B) having an N-linked side chain. In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include phenylalkylamines of formula (B), wherein the primary amine is substituted with a side chain as described in the embodiments herein.

[0116] Modification of the 2C aromatic ring at different positions produces distinct compounds with altered neurochemical effects. Many 2C compounds show affinity for different subtypes of the serotonin 5-HT2 receptor, and some interfere with the reuptake of dopamine, serotonin, and norepinephrine, while 2C-B acts as an α1-adrenergic receptor agonist (Nichols, Pharmacology & Therapeutics. 2004;101(2):131-181; Villalobos et al., British Journal of Pharmacology. 2004;141(7):1167-1174). In some embodiments, the substituted phenylalkylamine compounds of the present disclosure include 2C-X having an N-linked side chain, and 2C-X is 2C-B, 2C-B-AN, 2C-B-Butterfly, 2C-B-Fly-NBOMe, 2C-B-Fly-NB2EtO5Cl, 2C-Bn, 2C-Bu, 2C-B-5-Hemifly, 2C-C, 2C-C-3, 2C-CN, 2C-CP, 2C-D, 2C-E, 2C-EF, 2C-F, 2C-G, 2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, 2C-G-N, 2C-H, 2C-I, 2CB-Ind, 2C-iP, 2C-N, 2C-NH2, 2C-PYR, 2C-PIP, 2C-O, 2C-O-4, 2C-MOM, 2C-P, 2C-Ph, 2C-Se, 2C-T, 2C-T-2, 2C-T-3, 2C-T-4, 2C-T-5, 2C-T-6, 2C-T-7, 2C-T-8, 2C-T-9, 2C-T-10, 2C-T-11, 2C-T-12, 2C-T-13, 2C-T-14, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-18, 2C-T-19, 2C-T-21, 2C-T-21.5, 2C-T-22, 2C-T-23, 2C-T-24, 2C-T-25, 2C-T-27, 2C-T-28, 2C-T-30, 2C-T-31, 2C-T-32, 2C-T-33, 2C-DFM, 2C-TFM, 2C-TFE, 2C-YN, 2C-V, or 2C-AL, and such compounds are understood in the art and are amine-substituted with the side chains defined herein.

[0117] As used herein, in the context of the disclosed substituted phenylalkylamine compounds, the term "side chain" refers to an optionally substituted alkyl chain (e.g., optionally substituted n-decyl). In some embodiments, one or more methylene units of the alkyl chain may be replaced by a heteroatom (e.g., oxygen; thereby introducing an ether bond into the side chain). In some embodiments, the alkyl chain is substituted. For example, in some embodiments, the side chain is aryl-substituted (e.g., substituted with an optionally substituted phenyl ring).

[0118] In some embodiments, the side chain is -(CH2) m X(CH2) n has the structure of Ph, where X is methylene (CH2) or a heteroatom linker (e.g., O, S, NH, etc.); Ph is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and m and n are each independently an integer from 1 to 20. In some embodiments, X is CH2. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NH. In some embodiments, the side chain is aralkyloxyalkyl (e.g., -(CH2) m O(CH2) n has the formula of Ph), and the disclosed compounds are N-aralkyloxyalkyl-substituted phenylalkylamines.

[0119] In some embodiments, Ph is an optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In an embodiment, Ph is an optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl. In an embodiment, Ph is an optionally substituted aryl. In an embodiment, Ph is an optionally substituted phenyl. In an embodiment, Ph is unsubstituted phenyl. In an embodiment, Ph is phenyl substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0120] In some embodiments, m is an integer from 1 to 20. In an embodiment, m is 1. In an embodiment, m is 2. In an embodiment, m is 3. In an embodiment, m is 4. In an embodiment, m is 5. In an embodiment, m is 6. In an embodiment, m is 7. In an embodiment, m is 8. In an embodiment, m is 9. In an embodiment, m is 10. In an embodiment, m is 11. In an embodiment, m is 12. In an embodiment, m is 13. In an embodiment, m is 14. In an embodiment, m is 15. In an embodiment, m is 16. In an embodiment, m is 17. In an embodiment, m is 18. In an embodiment, m is 19. In an embodiment, m is 20. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4. In an embodiment, n is 5. In an embodiment, n is 6. In an embodiment, n is 7. In an embodiment, n is 8. In an embodiment, n is 9. In an embodiment, n is 10. In an embodiment, n is 11. In an embodiment, n is 12. In an embodiment, n is 13. In an embodiment, n is 14. In an embodiment, n is 15. In an embodiment, n is 16. In an embodiment, n is 17. In an embodiment, n is 18. In an embodiment, n is 19. In an embodiment, n is 20. In an embodiment, the sum of m + n is from 4 to 16. In an embodiment, the sum of m + n is from 6 to 14. In an embodiment, the sum of m + n is from 7 to 13. In an embodiment, the sum of m + n is from 8 to 12. In an embodiment, the sum of m + n is from 9 to 11. In an embodiment, the sum of m + n is 6. In an embodiment, the sum of m + n is 7. In an embodiment, the sum of m + n is 8. In an embodiment, the sum of m + n is 9. In an embodiment, the sum of m + n is 10. In an embodiment, the sum of m + n is 11. In an embodiment, the sum of m + n is 12. In an embodiment, the sum of m + n is 13. In an embodiment, the sum of m + n is 14. In an embodiment, m and n are selected from the following pairs: 1 and 9, 2 and 8, 3 and 7, 4 and 6, 5 and 5, 6 and 4, 7 and 3, 8 and 2, 9 and 1.

[0121] In some embodiments, the compound has the structure of formula (I),

Chemical formula

[0122] In embodiments, m and n are selected from the following pairs of series: 1 and 9, 2 and 8, 3 and 7, 4 and 6, 5 and 5, 6 and 4, 7 and 3, 8 and 2, 9 and 1. In embodiments, m is 1 and n is 9. In embodiments, m is 2 and n is 8. In embodiments, m is 3 and n is 7. In embodiments, m is 4 and n is 6. In embodiments, m is 5 and n is 5. In embodiments, m is 6 and n is 4. In embodiments, m is 7 and n is 3. In embodiments, m is 8 and n is 2. In embodiments, m is 9 and n is 1.

[0123] In some embodiments, R and R2 are independently hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, any of which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is hydrogen. In an embodiment, R is C1-C8 alkyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is unsubstituted C1-C8 alkyl. In an embodiment, R is substituted C1-C8 alkyl. In an embodiment, R is C1-C8 alkoxy which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is unsubstituted C1-C8 alkoxy. In an embodiment, R is substituted C1-C8 alkoxy.In an embodiment, R is a C1-C8 alkenyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted C1-C8 alkenyl. In an embodiment, R is a substituted C1-C8 alkenyl. In an embodiment, R is a C1-C8 alkynyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted C1-C8 alkynyl. In an embodiment, R is a substituted C1-C8 alkynyl. In an embodiment, R is a C3-C8 cycloalkyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted C3-C8 cycloalkyl. In an embodiment, R is a substituted C3-C8 cycloalkyl. In an embodiment, R is a C3-C8 cycloalkenyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.In an embodiment, R is an unsubstituted C3-C8 cycloalkenyl. In an embodiment, R is a substituted C3-C8 cycloalkenyl. In an embodiment, R is an aryl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted aryl. In an embodiment, R is a substituted aryl. In an embodiment, R is a heterocyclyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is an unsubstituted heterocyclyl. In an embodiment, R is a substituted heterocyclyl.

[0124] In some embodiments, R2 is hydrogen. In an embodiment, R2 is a C1-C8 alkyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is an unsubstituted C1-C8 alkyl. In an embodiment, R2 is a substituted C1-C8 alkyl. In an embodiment, R2 is a C1-C8 alkoxy optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is an unsubstituted C1-C8 alkoxy. In an embodiment, R2 is a substituted C1-C8 alkoxy. In an embodiment, R2 is a C1-C8 alkenyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is an unsubstituted C1-C8 alkenyl. In an embodiment, R2 is a substituted C1-C8 alkenyl. In an embodiment, R2 is a C1-C8 alkynyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.In an embodiment, R2 is unsubstituted C1-C8 alkynyl. In an embodiment, R2 is substituted C1-C8 alkynyl. In an embodiment, R2 is C3-C8 cycloalkyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is unsubstituted C3-C8 cycloalkyl. In an embodiment, R2 is substituted C3-C8 cycloalkyl. In an embodiment, R2 is C3-C8 cycloalkenyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is unsubstituted C3-C8 cycloalkenyl. In an embodiment, R2 is substituted C3-C8 cycloalkenyl. In an embodiment, R2 is aryl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is unsubstituted aryl. In an embodiment, R2 is substituted aryl.In an embodiment, R2 is a heterocyclyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is an unsubstituted heterocyclyl. In an embodiment, R2 is a substituted heterocyclyl.

[0125] In some embodiments, R1 represents one to three substituents independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano and nitrate. In an embodiment, R1 represents one substituent selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano and nitrate. In an embodiment, R1 represents two substituents independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano and nitrate.In an embodiment, R1 represents three substituents independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano and nitrate.

[0126] In some embodiments, R1 is hydrogen. In an embodiment, R1 is a halogen. In an embodiment, R1 is F, Cl, Br, or I. In an embodiment, R1 is a C1-C8 alkyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In an embodiment, R1 is an unsubstituted C1-C8 alkyl. In an embodiment, R1 is a substituted C1-C8 alkyl. In an embodiment, R1 is a C1-C8 alkoxy optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In an embodiment, R1 is an unsubstituted C1-C8 alkoxy. In an embodiment, R1 is a substituted C1-C8 alkoxy. In an embodiment, R1 is a C1-C8 alkenyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In an embodiment, R1 is an unsubstituted C1-C8 alkenyl. In an embodiment, R1 is a substituted C1-C8 alkenyl.In an embodiment, R1 is C1-C8 alkynyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is unsubstituted C1-C8 alkynyl. In an embodiment, R1 is substituted C1-C8 alkynyl. In an embodiment, R1 is C3-C8 cycloalkyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is unsubstituted C3-C8 cycloalkyl. In an embodiment, R1 is substituted C3-C8 cycloalkyl. In an embodiment, R1 is C3-C8 cycloalkenyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is unsubstituted C3-C8 cycloalkenyl. In an embodiment, R1 is substituted C3-C8 cycloalkenyl. In an embodiment, R1 is aryl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.In an embodiment, R1 is an unsubstituted aryl. In an embodiment, R1 is a substituted aryl. In an embodiment, R1 is a heterocyclyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is an unsubstituted heterocyclyl. In an embodiment, R1 is a substituted heterocyclyl.

[0127] In some embodiments, R3 is hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; or R3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano and nitrate.

[0128] In some embodiments, R3 is hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate. In an embodiment, R3 is hydrogen. In an embodiment, R3 is C1-C8 alkyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is unsubstituted C1-C8 alkyl. In an embodiment, R3 is substituted C1-C8 alkyl. In an embodiment, R3 is C1-C8 alkoxy which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is unsubstituted C1-C8 alkoxy. In an embodiment, R3 is substituted C1-C8 alkoxy.In an embodiment, R3 is a C1-C8 alkenyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is an unsubstituted C1-C8 alkenyl. In an embodiment, R3 is a substituted C1-C8 alkenyl. In an embodiment, R3 is a C1-C8 alkynyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is an unsubstituted C1-C8 alkynyl. In an embodiment, R3 is a substituted C1-C8 alkynyl. In an embodiment, R3 is a C3-C8 cycloalkyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is an unsubstituted C3-C8 cycloalkyl. In an embodiment, R3 is a substituted C3-C8 cycloalkyl. In an embodiment, R3 is a C3-C8 cycloalkenyl which may be substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.In an embodiment, R3 is an unsubstituted C3-C8 cycloalkenyl. In an embodiment, R3 is a substituted C3-C8 cycloalkenyl. In an embodiment, R3 is an aryl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is an unsubstituted aryl. In an embodiment, R3 is a substituted aryl. In an embodiment, R3 is a heterocyclyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R3 is an unsubstituted heterocyclyl. In an embodiment, R3 is a substituted heterocyclyl.

[0129] In some embodiments, R3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano and nitrate. In an embodiment, R3 is halogen. In an embodiment, R3 is alkyl. In an embodiment, R3 is alkyl ester. In an embodiment, R3 is hydroxy. In an embodiment, R3 is alkoxy. In an embodiment, R3 is carboxy. In an embodiment, R3 is formyl. In an embodiment, R3 is aryloxy. In an embodiment, R3 is amino. In an embodiment, R3 is alkylamino. In an embodiment, R3 is arylamide. In an embodiment, R3 is alkylamide. In an embodiment, R3 is thiol. In an embodiment, R3 is thioalkyl. In an embodiment, R3 is thioaryl. In an embodiment, R3 is alkylsulfonyl. In an embodiment, R3 is alkylcarbamoyl. In an embodiment, R3 is arylcarbamoyl. In an embodiment, R3 is nitro. In an embodiment, R3 is cyano. In an embodiment, R3 is nitrate.

[0130] In some embodiments, Ph is phenyl optionally substituted at one or more positions by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano and nitrate. In an embodiment, Ph is unsubstituted phenyl. In an embodiment, Ph is substituted phenyl.

[0131] Exemplary side chain variants of formula (I) are shown in Table 1, which, according to the embodiments of the present specification, can be, for example, as individual compounds, as part of a composition containing individual compounds, as part of a composition containing a mixture of two (or more) compounds, and for use in preparing pharmaceuticals for treatment or for methods of regulating neurotransmission, treating medical conditions or ameliorating their symptoms, and / or improving mental health or function (as such compounds and / or compositions), and can be claimed as such compounds and / or compositions. [Table 2]

[0132] In some embodiments, the compound has the formula (II): [Chemical formula] (wherein, m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is O, S or NH; R and R2 are each independently C1-C8 alkoxy, and each C1-C8 alkoxy may be substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R1 is selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, and each of these may be substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R3 is hydrogen or C1-C8 alkyl; and Ph is phenyl which may be substituted by halogen, azide, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate) or has a structure of its pharmaceutically acceptable salt.

[0133] In some embodiments, m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In an embodiment, m is 1. In an embodiment, m is 2. In an embodiment, m is 3. In an embodiment, m is 4. In an embodiment, m is 5. In an embodiment, m is 6. In an embodiment, m is 7. In an embodiment, m is 8. In an embodiment, m is 9. In an embodiment, m is 10. In an embodiment, m is 11. In an embodiment, m is 12. In an embodiment, m is 13. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4. In an embodiment, n is 5. In an embodiment, n is 6. In an embodiment, n is 7. In an embodiment, n is 8. In an embodiment, n is 9. In an embodiment, n is 10. In an embodiment, n is 11. In an embodiment, n is 12. In an embodiment, n is 13. In an embodiment, the sum of m + n is from 6 to 14. In an embodiment, the sum of m + n is from 7 to 13. In an embodiment, the sum of m + n is from 8 to 12. In an embodiment, the sum of m + n is from 9 to 11. In an embodiment, the sum of m + n is 6. In an embodiment, the sum of m + n is 7. In an embodiment, the sum of m + n is 8. In an embodiment, the sum of m + n is 9. In an embodiment, the sum of m + n is 10. In an embodiment, the sum of m + n is 11. In an embodiment, the sum of m + n is 12. In an embodiment, the sum of m + n is 13. In an embodiment, the sum of m + n is 14.

[0134] In some embodiments, X is O, S or NH. In an embodiment, X is O. In an embodiment, X is S. In an embodiment, X is NH.

[0135] In some embodiments, R and R2 are each independently C1-C8 alkoxy, and each C1-C8 alkoxy may be substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R is C1-C8 alkoxy. In an embodiment, R is methoxy (-OCH3). In an embodiment, R is unsubstituted C1-C8 alkoxy. In an embodiment, R is C1-C8 alkoxy and the C1-C8 alkoxy is substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R2 is C1-C8 alkoxy. In an embodiment, R2 is methoxy (-OCH3). In an embodiment, R2 is unsubstituted C1-C8 alkoxy. In an embodiment, R2 is C1-C8 alkoxy and the C1-C8 alkoxy is substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0136] In some embodiments, R1 is selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, each of which may be substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is hydrogen. In an embodiment, R1 is halogen. In an embodiment, R1 is F, Cl, Br or I. In an embodiment, R1 is F. In an embodiment, R1 is Cl. In an embodiment, R1 is Br. In an embodiment, R1 is I. In an embodiment, R1 is C1-C8 alkyl. In an embodiment, R1 is methyl (-CH3) or ethyl (-CH2CH3). In an embodiment, R1 is methyl. In an embodiment, R1 is ethyl. In an embodiment, R1 is unsubstituted C1-C8 alkyl. In an embodiment, R1 is C1-C8 alkyl substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is C1-C8 alkoxy. In an embodiment, R1 is methoxy (-OCH3). In an embodiment, R1 is ethoxy (-OCH2CH3). In an embodiment, R1 is unsubstituted C1-C8 alkoxy.In an embodiment, R1 is C1-C8 alkoxy substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is C1-C8 thioalkyl. In an embodiment, R1 is methylthio (-SCH3). In an embodiment, R1 is ethylthio (-SCH2CH3). In an embodiment, R1 is unsubstituted C1-C8 thioalkyl. In an embodiment, R1 is C1-C8 thioalkyl substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is C2-C8 alkenyl. In an embodiment, R1 is unsubstituted C1-C8 alkenyl. In an embodiment, R1 is C1-C8 alkenyl substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is C2-C8 alkynyl. In an embodiment, R1 is unsubstituted C1-C8 alkynyl. In an embodiment, R1 is C1-C8 alkynyl substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is C3-C8 cycloalkyl.In an embodiment, R1 is unsubstituted C3-C8 cycloalkyl. In an embodiment, R1 is C3-C8 cycloalkyl substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is C3-C8 cycloalkenyl. In an embodiment, R1 is aryl. In an embodiment, R1 is unsubstituted aryl. In an embodiment, R1 is aryl substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, R1 is heterocyclyl. In an embodiment, R1 is unsubstituted heterocyclyl. In an embodiment, R1 is heterocyclyl substituted with halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate.

[0137] In some embodiments, R3 is hydrogen or C1-C8 alkyl. In an embodiment, R3 is hydrogen. In an embodiment, R3 is C1-C8 alkyl. In an embodiment, R3 is methyl (-CH3) or ethyl (-CH2CH3). In an embodiment, R3 is methyl. In an embodiment, R3 is ethyl.

[0138] In an embodiment, Ph is phenyl which may be substituted by halogen, azide, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, Ph is phenyl. In an embodiment, Ph is unsubstituted phenyl. In an embodiment, Ph is phenyl substituted by halogen, azide, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate. In an embodiment, Ph is phenyl substituted by halogen. In an embodiment, Ph is phenyl substituted by F, Cl, Br or I. In an embodiment, Ph is phenyl substituted by azide. In an embodiment, Ph is phenyl substituted by alkyl. In an embodiment, Ph is phenyl substituted by alkyl ester. In an embodiment, Ph is phenyl substituted by hydroxy. In an embodiment, Ph is phenyl substituted by alkoxy. In an embodiment, Ph is phenyl substituted by methoxy. In an embodiment, Ph is phenyl substituted by carboxy. In an embodiment, Ph is phenyl substituted by formyl. In an embodiment, Ph is phenyl substituted by aryl. In an embodiment, Ph is phenyl substituted by heterocyclyl. In an embodiment, Ph is phenyl substituted by amino. In an embodiment, Ph is phenyl substituted by alkylamino. In an embodiment, Ph is phenyl substituted by arylamide. In an embodiment, Ph is phenyl substituted by alkylamide. In an embodiment, Ph is phenyl substituted by thiol. In an embodiment, Ph is phenyl substituted by thioalkyl. In an embodiment, Ph is phenyl substituted by thioaryl.In an embodiment, Ph is phenyl substituted with alkylsulfonyl. In an embodiment, Ph is phenyl substituted with alkylcarbamoyl. In an embodiment, Ph is phenyl substituted with arylcarbamoyl. In an embodiment, Ph is phenyl substituted with nitro. In an embodiment, Ph is phenyl substituted with cyano. In an embodiment, Ph is phenyl substituted with nitrato.

[0139] In some embodiments, the compound has a structure of formula (IIA), (IIB) or (IIC) as shown in Table 2 below, wherein m, n, X and Ph are as defined above for formula (II). [Table 3]

[0140] In some embodiments, the compound has a structure of any of formulas (III) to (XXVI) as shown in Table 3 below. [Table 4-1] [Table 4-2] [Table 4-3]

[0141] In some embodiments, the compound is selected from Table 4 and the compound has the following structure, wherein R, R1, R2, R3, m, X, n and Ph are as defined in the table: [Chemical Formula] [Table 5-1] [Table 5-2]

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

Table 5-15

Table 5-16

Table 5-17

Table 5-18

Table 5-19

Table 5-20

Table 5-21

Table 5-22

Table 5-23

Table 5-24

Table 5-25

Table 5-26

Table 5-27

Table 5-28

Table 5-29

Table 5-30

Table 5-31

Table 5-32

Table 5-33

Table 5-34

Table 5-35

[0142] In some embodiments, the compound is

Table 6

[0143] In some embodiments, the compound is

Chemical Structure

[0144] Each individual compound of the disclosed composition is understood to include also the pharmaceutically acceptable salts of such compounds. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases and which can be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base forms of these agents with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent, or in a mixture of the two; generally, a non-aqueous medium (e.g., ether, ethyl acetate, ethanol, isopropanol or acetonitrile) is preferred. For therapeutic use, the salts of the compounds are those in which the counterion is pharmaceutically acceptable. One of ordinary skill in the art can select a pharmaceutically acceptable one from among the various available counterions. In certain applications, the selection of a given anion or cation for the preparation of a salt can result in an increase or decrease in the solubility of that salt. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-naphthylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefilinate, acetate, acetyurate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, cancilate, carbonate, cholate, citrate, clavulanate, cyclopentanepropionate, cypionate, d-aspartate, d-cancilate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylicate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisinate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycolylarsanilate, hemisulfate,Heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hibenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulfonate, lithium, magnesium, malate, maleate, malonate, mandelate, mesotartrate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisylate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphate|diphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharinate, salicylate, salicylsulfate, sodium, stearate, basic acetate, succinate, sulfate, sulfosalicylate, sulfosalicylate, suramate, tannate, tartrate, theophylline, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc, etc. (see Berge, et al., J. Pharm. Sci. 1997, 66, 1-19).

[0145] The specific compounds disclosed herein contain one or more ionizable groups (groups capable of removing (e.g., -COOH) or adding (e.g., an amine) a proton, or of quaternizing (e.g., an amine)). All possible ionic forms of such molecules and their salts are included in this disclosure.

[0146] The compounds described herein can exist in solid or liquid form. In the solid state, the compound can exist in crystalline or amorphous form, or as a mixture thereof. One of ordinary skill in the art will understand that pharmaceutically acceptable solvates can be formed for crystalline or amorphous compounds. In a crystalline solvate, solvent molecules are incorporated into the crystal lattice during crystallization. The solvate may include a non-aqueous solvent such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or may include water as the solvent incorporated into the crystal lattice. A solvate in which water is the incorporated solvent is typically referred to as a “hydrate”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The subject matter described herein includes such solvates.

[0147] One of ordinary skill in the art will further understand that the specific compounds described herein, which exist in crystalline form including their various solvates, may exhibit polymorphism (i.e., the ability to exist in different crystal structures). These different crystal forms are typically known as “polymorphs”. The subject matter disclosed herein includes such polymorphs. Polymorphs include different crystal packing arrangements of a compound of the same elemental composition. Polymorphs have the same chemical composition but differ in the packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution characteristics. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. One of ordinary skill in the art will understand that different polymorphs can be produced, for example, by changing or adjusting the reaction conditions or reagents used in the manufacture of the compound. For example, changes in temperature, pressure, or solvent can result in polymorphs. Various factors such as the recrystallization solvent, crystallization rate, and storage temperature can dominate the single crystal form. Furthermore, one polymorph may spontaneously convert to another polymorph under certain conditions.

[0148] The compounds described herein may contain one or more asymmetric centers and can give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center can be defined as (R)- or (S)- with respect to the absolute stereochemistry. The present invention includes all such possible isomers, as well as racemic and optically pure forms and mixtures thereof. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. Various methods for preparing optically active forms and determining activity are known in the art. Such methods include the standard tests described herein and other similar tests well known in the art. Examples of methods that can be used to obtain the optical isomers of the compounds according to the present disclosure include selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzymatic synthesis), kinetic resolution, and chiral chromatography (including chiral liquid chromatography, gas chromatography, and high performance liquid chromatography). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, tautomeric forms are included.

[0149] Compounds having at least one desired isotope substitution of an atom in an amount exceeding the natural abundance of the isotope, i.e., isotopically enriched analogs of the disclosed compounds, are also provided. Isotopes are atoms having the same atomic number but different mass numbers, i.e., atoms having the same number of protons but different numbers of neutrons. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O and 36 Cl, respectively. In one non-limiting embodiment, the isotopically labeled compound is for metabolic studies (14 using C), reaction kinetics studies (e.g., 2 H or 3 using H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or can be used for radiotherapy of patients. In particular, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2 H, can result in greater metabolic stability, such as an increase in in vivo half-life or a decrease in required dosage, and thus may be preferred in some situations. The isotope-labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations by using readily available isotope-labeled reagents in place of non-isotope-labeled reagents.

[0150] Prodrugs of the disclosed compounds are also provided. A "prodrug" is a precursor of a biologically active pharmaceutical that can undergo chemical or metabolic transformation to become a biologically active agent. A prodrug can be converted ex vivo to a biologically active pharmaceutical by a chemical conversion process. In vivo, a prodrug is converted to a biologically active pharmaceutical by the action of a metabolic, enzymatic, or degradative process that removes the prodrug moiety to form the biologically active pharmaceutical. Typical examples of prodrugs include compounds having a biologically labile or cleavable (protecting) group on a functional moiety of an active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolized, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Commonly used functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides. These functional groups can be attached to the drug molecule via a linker designed to be cleaved under specific physiological conditions such as enzymatic hydrolysis or pH-dependent cleavage. The choice of functional group depends on factors such as stability, ease of synthesis, enzymatic activity, and the desired prodrug conversion rate.

[0151] Generally, the individual compounds disclosed are administered as part of a pharmaceutical composition or formulation and are prepared for inclusion in such a composition or formulation as an isolated or purified compound. As used herein, the terms “isolated,” “purified,” or “substantially pure” refer to a material that is substantially or essentially free of the components that are normally associated with the material when it is produced by synthesis, manufacture, or other means. Thus, an “isolated,” “purified,” or “substantially pure” preparation of a compound is defined as a preparation having a chromatographic purity of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9% (of the desired compound), as determined by area normalization of an HPLC profile or other similar detection method.

[0152] Preferably, the substantially pure compounds of the present disclosure are substantially free of any other active compounds that are not intended to be administered to a subject. In this regard, “substantially free of” can be interpreted to mean that the active compounds other than the active compound intended to be administered to the subject are not detectable by HPLC or other similar detection methods, or are below the desired detection threshold as defined above.

[0153] C. Pharmaceutical Compositions In some aspects, provided herein are compositions, e.g., pharmaceutical compositions, comprising a disclosed compound, e.g., a compound of any disclosed formula or a sub-formula thereof. A “pharmaceutical composition” is a composition that comprises a disclosed compound in a quantity (e.g., in unit dosage form) together with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments include a plurality of carriers, diluents, and / or excipients rather than a single carrier, diluent, or excipient alone. The compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub.Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub.Co., Inc., Lancaster, Pa.; and Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; and Poznansky et al. Drug Delivery Systems (1980), R.L. Juliano, ed., Oxford, N.Y., pp. 253 - 315).

[0154] “Pharmaceutically acceptable” when used in reference to an excipient, carrier, diluent, or other ingredient means that the ingredient is generally safe, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio.

[0155] In some embodiments, pharmaceutical compositions containing the disclosed compounds can be administered by various routes including oral, mucosal (e.g., oral, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal. In some embodiments, the compounds used in the methods of the invention are effective as oral, mucosal (e.g., oral, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhalation, and intranasal compositions. Such compositions are prepared by methods well known in the pharmaceutical art and contain at least one active compound (see, e.g., Remington, 2020).

[0156] The disclosed compositions are preferably formulated into unit dosage forms, and each dosage contains a therapeutically effective amount of the active ingredient, for example, in the dosages disclosed below. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for the subject to be treated, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and uniformity of dosage. A unit dosage form can include a single or individual dose or unit, sub-dose, or appropriate fraction (e.g., half of a "complete" dose for a "booster" dose as described below) of the pharmaceutical composition to be administered.

[0157] Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules, and vials, which may include compositions in freeze-dried or lyophilized form; for example, a sterile liquid carrier can be added before in vivo administration or delivery. Unit dosage forms also include ampules and vials in which a liquid composition is disposed. Unit dosage forms further include compounds for transdermal administration, e.g., "patches" that contact the epidermis (including mucosa) of the subject for a long or short period.

[0158] In some embodiments, the disclosed compositions are formulated into pharmaceutically acceptable oral dosage forms. Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, etc.) as well as oral solid dosage forms. The disclosed pharmaceutical compositions can also be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, including physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0159] In some embodiments, the disclosed compositions are formulated as oral solid dosage forms. Oral solid dosage forms can include, but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combination thereof. Oral solid dosage forms can be formulated as immediate release, controlled release, sustained release formulations, extended release, or modified release formulations. Thus, in some embodiments, the disclosed oral solid dosage forms can be in the form of tablets (including suspension tablets, fast-dissolving tablets, chewable disintegrating tablets, fast-disintegrating tablets, effervescent tablets or caplets), pills, powders (including sterile packaged powders, dispensable powders, or effervescent powders), capsules (both soft capsules or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulsed release dosage forms, multiparticulate dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet including fast-dissolving tablets. Further, the pharmaceutical formulation can be administered as a single capsule dosage form or in multiple capsule dosage forms. In some embodiments, the pharmaceutical formulation is administered in 2, 3, 4, or more capsules or tablets.

[0160] Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersants, suspending agents, disintegrants, thickeners, film-forming agents, granulation aids, flavoring agents, sweetening agents, coating agents, solubilizing agents, and combinations thereof. Oral solid dosage forms may also contain, alone or in combination, one or more pharmaceutically acceptable additives such as compatibility carriers, complexing agents, ionic dispersion regulators, disintegrants, surfactants, lubricants, coloring agents, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, etc., and co-active compound(s).

[0161] Co-active compounds include preservatives, antioxidants, antimicrobials including biocides and biostats, such as antibacterial agents, antiviral agents, and antifungal agents. Preservatives can be used to inhibit the growth of microorganisms or increase the stability of the active ingredient, thereby extending the shelf life of the formulation. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride, or benzoates such as benzoic acid or sodium benzoate. Antioxidants include compounds such as vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherol, other vitamins or provitamins, and alpha-lipoic acid.

[0162] In some embodiments, the disclosed compositions are formulated as oral liquid dosage forms. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, etc. These oral liquid dosage forms can be formulated using any pharmaceutically acceptable excipients known to those skilled in the art for preparing liquid dosage forms, as well as solvents, diluents, carriers, excipients, etc. selected to be appropriate for the solubility and other properties of the active drug and other ingredients. The solvent can be, for example, water, glycerin, simple syrup, alcohol, medium-chain triglycerides (MCT), and combinations thereof.

[0163] Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions that may contain an inert diluent such as water. Pharmaceutical formulations can be prepared as liquid suspensions or solutions using sterile liquids such as, but not limited to, oils, water, alcohols, and combinations of these pharmaceutically suitable surfactants, suspending agents, and emulsifying agents can be added for oral or parenteral administration. Liquid formulations can also be prepared as single-dose or multi-dose beverages. Suspensions can contain oil. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT oil and long-chain triglyceride (LCT) oil. Suspension formulations can also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations can contain alcohols (such as ethanol, isopropyl alcohol, hexadecyl alcohol, etc.), glycerol, and propylene glycol. Ethers such as polyethylene glycol, petroleum hydrocarbons such as mineral oil and petrolatum, and water can also be used in suspension formulations. Thus, suspensions can include aqueous liquids or non-aqueous liquids, oil-in-water liquid emulsions, or water-in-oil emulsions.

[0164] In some embodiments, a formulation is provided that includes the disclosed composition and at least one dispersing or suspending agent for oral administration to a subject. The formulation can be a powder and / or granule for suspension that, when mixed with water, provides a substantially uniform suspension. The aqueous dispersion can include amorphous particles and non-amorphous particles having a plurality of effective particle sizes such that the drug is absorbed in a controlled manner over time.

[0165] Dosage forms for oral administration can be aqueous suspensions selected from the group consisting of pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, for example, Singh et al., Encyclopedia of Pharm. Tech., 2nd Ed., 754-757 (2002). In addition to the disclosed compounds, liquid dosage forms can include additives such as one or more of (a) disintegrants, (b) dispersants, (c) wetting agents, (d) preservatives, (e) thickeners, (f) sweeteners, or (g) flavoring agents.

[0166] The disclosed compositions can also be prepared as formulations suitable for intramuscular, subcutaneous, intraperitoneal, or intravenous injection, including physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0167] In other embodiments, the disclosed pharmaceutical compositions can be formulated into topical dosage forms. Topical dosage forms include transmucosal and transdermal formulations such as aerosols, emulsions, sprays, ointments, plasters, gels, pastes, lotions, liniments, oils, and creams. For such formulations, permeation enhancers and carriers can be included in the pharmaceutical composition. Permeation enhancers are known in the art and include detergents, bile salts, and fusidic acid derivatives for transmucosal administration. For transdermal administration, carriers that can be used include Vaseline®, lanolin, PEG, alcohols, transdermal absorption promoters, and combinations thereof.

[0168] D. Combinations of Pharmaceuticals The disclosed compositions are not limited to a combination of a single compound or, when formulated as a pharmaceutical composition, to only a single carrier, diluent, and / or excipient, and can readily be understood to include combinations of a plurality of compounds (including additional active compounds), and / or combinations of a plurality of carriers, diluents, and excipients. Accordingly, the pharmaceutical compositions of the present invention can include a compound of formula (I) in combination with one or more other active agents (or derivatives and analogs thereof) together with one or more pharmaceutically acceptable carriers, diluents, and / or excipients, and further together with one or more other active compounds.

[0169] In some embodiments, the formulations of the present invention are prepared to increase existing therapeutic effects, provide additional therapeutic effects, increase desired properties such as stability or shelf life, decrease undesirable actions or properties, vary properties in a desired manner (e.g., pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., neurotransmission systems), or provide a synergistic effect.

[0170] "Therapeutic effects" that can be increased or added in embodiments of the present invention include, but are not limited to, antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anti-anxiety, anti-depressant, anti-psychotic, anti-PTSD, dissociative facilitation, immunostimulatory, anti-cancer, anti-emetic, appetite promoting, anti-ulcer, anti-histamine, anti-hypertensive, anti-spasmodic, anti-epileptic, bronchodilatory, neuroprotective, empathogenic, psychedelic, sedative, and stimulatory effects.

[0171] "Synergistic effect" should be understood to include an increase in potency, biological activity, bioaccessibility, bioavailability, or therapeutic effect that is greater than the additive contributions of the components acting alone. There are numerous methods known to those skilled in the art for determining whether there is a synergistic effect with respect to a particular effect, i.e., whether when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby resulting in "1 + 1 > 2". Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019; 10:1222), or the Loewe additivity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313 - 326). Synergistic effects can also be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429 - 453) and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27 - 55). The corresponding graphs related to the equations mentioned above are concentration-effect curves and combination index curves, respectively. Applying each of the equations mentioned above to experimental data can create the corresponding graphs and assist in the evaluation of the effects of drug combinations.

[0172] In some embodiments, the disclosed pharmaceutical composition comprises an additional active compound. In some embodiments, the additional active compound is selected from the group consisting of amino acids, antioxidants, anti - inflammatory agents, analgesics, anti - neuropathic and anti - nociceptive agents, anti - migraine agents, anxiolytics, antidepressants, antipsychotics, anti - PTSD agents, dissociative agents, cannabinoids, immunostimulants, anti - cancer agents, anti - emetics, appetite stimulants, anti - ulcer agents, anti - histamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotective agents, nootropics, empathogens, psychedelic drugs, plasticity enhancers (e.g., psychoplastogens), monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonin agonists, and vitamins. In some embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, reduce an undesirable effect, increase stability or shelf life, improve bioavailability, induce a synergistic effect, increase plasticity (e.g., neural plasticity), or alter pharmacokinetics or pharmacodynamics. In some embodiments, the additional therapeutic effect is an antioxidant effect, anti - inflammatory effect, analgesic effect, anti - neuropathic effect, anti - nociceptive effect, anti - migraine effect, anxiolytic effect, antidepressant effect, antipsychotic effect, anti - PTSD effect, dissociative - promoting effect, immunostimulant effect, anti - cancer effect, anti - emetic effect, appetite - stimulating effect, anti - ulcer effect, anti - histamine effect, antihypertensive effect, anticonvulsant effect, antiepileptic effect, bronchodilator effect, neuroprotective effect, empathogenic effect, psychedelic effect, sedative effect, or stimulant effect.

[0173] In an embodiment, the additional active compound is tryptamine. As will be understood by those skilled in the art, tryptamine is a compound having the following general structure, where R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 are as defined herein and as generally understood in the art: [Chemical formula]

[0174] In some embodiments, R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, deuterium, halogen (F, Cl, Br or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Further, any two of R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 can combine with intervening atoms to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In an embodiment, tryptamine is a quaternary salt in which R N1 and R N2 are bonded to the nitrogen to which an additional R N3 is attached; R N3 is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0175] In some embodiments, additional active compounds are O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 6-allyl-N,N-diethyl-norlysergamide (AL-LAD), N,N-dibutyltryptamine (DBT), N,N-diethyltryptamine (DET), N,N-diisopropyltryptamine (DiPT), 5-methoxy-α-methyltryptamine (α,O-DMS), N,N-dimethyltryptamine (DMT), 2,α-dimethyltryptamine (2,α-DMT), α,N-dimethyltryptamine (α,N-DMT), N,N-dipropyltryptamine (DPT), N-ethyl-N-isopropyltryptamine (EiPT), α-ethyltryptamine (AET), 6,N,N-triethylnorlysergamide (ETH-LAD), 3,4-dihydro-7-methoxy-1-methylcarboline (harmaline), 7-methoxy-1-methylcarboline (harmine), N,N-dibutyl-4-hydroxy-tryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl-4-hydroxytryptamine (4-HO-DiPT), 4-hydroxy-N,N,N-trimethyltryptamine (4-HO-TMT), N,N-dimethyl-4-hydroxytryptamine (4-HO-DMT), N,N-dimethyl-5-hydroxytryptamine (5-HO-DMT, bufotenin), N,N-dipropyl-4-hydroxytryptamine (4-HO-DPT), N-ethyl-4-hydroxy-N-methyltryptamine (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyltryptamine (4-HO-MiPT), 4-hydroxy-N-methyl-N-propyl-tryptamine (4-HO-MPT), 4-hydroxy-N,N-tetramethylene-tryptamine (4-HO-pyr-T), 12-methoxyibogamine (ibogaine), N-butyl-N-methyltryptamine (MBT), N,N-diisopropyl-4,5-methylenedioxytryptamine (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxytryptamine (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxytryptamine (4,5-MDO-DMT), N,N-dimethyl-5,6-Methylenedioxytriptamine (5,6-MDO-DMT), N-isopropyl-N-methyl-5,6-methylenedioxytriptamine (5,6-MDO-MiPT), N,N-diethyl-2-methyltriptamine (2-Me-DET), 2,N,N-trimethyltriptamine (2-Me-DMT), N-acetyl-5-methoxytriptamine (melatonin), N,N-diethyl-5-methoxytriptamine (5-MeO-DET), N,N-diisopropyl-5-methoxy-triptamine (5-MeO-DiPT), N,N,diallyl-5-methoxytriptamine (5-MeO-DALT), 5-methoxy-N,N-dimethyltriptamine (5-MeO-DMT), N-isopropyl-4-methoxy-N-methyltriptamine (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyltriptamine (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyltriptamine (5,6-MeO-MiPT), 5-methoxy-N-methyl-triptamine (5-MeO-NMT), 5-methoxy-N,N-tetramethylenetriptamine (5-MeO-pyr-T), 6-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl-triptamine (5-MeO-TMT), N,N-dimethyl-5-methylthiotriptamine (5-MeS-DMT), N-isopropyl-N-methyltriptamine (MiPT), α-methyltriptamine (α-MT), N-ethyltriptamine (NET), N-methyltriptamine (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetramethylenetriptamine (pyr-T), tryptamine (T), 7-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (THH), or α,N-dimethyl-5-methoxytriptamine (α,N,O-TMS), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, or a combination thereof, and is a tryptamine selected from the group consisting of.,

[0176] In some embodiments, the additional tryptamine is "complex tryptamine" or another indoleamine, and examples include iboga alkaloids such as ibogaine, and their analogs, metabolites and derivatives, and β-carboline.

[0177] In some embodiments, the additional active compound is phenethylamine. In some embodiments, as would be understood by one of ordinary skill in the art, phenethylamine can be a phenylalkylamine having the structure of formula (A), where R N1 , R N2 , R α , R β , and R 2 ~R 6 each is as defined herein and as generally understood in the art.

[0178] In some embodiments, the additional active compounds are α-ethyl-3,4,5-trimethoxy-phenethylamine (AEM), 4-allyloxy-3,5-dimethoxyphenethylamine (AL), 2,5-dimethoxy-4-methylthioamphetamine (ALEPH), 2,5-dimethoxy-4-ethylthioamphetamine (ALEPH-2), 2,5-dimethoxy-4-isopropylthioamphetamine (ALEPH-4), 2,5-dimethoxy-4-phenylthio-amphetamine (ALEPH-6), 2,5-dimethoxy-4-propylthioamphetamine (ALEPH-7), 2,5-dimethoxy-α-ethyl-4-methylphenethylamine (ARIADNE), 3,4-diethoxy-5-methoxy-phenethylamine (ASB), 4-butoxy-3,5-dimethoxyphenethylamine (B), 2,5-dimethoxy-4,N-dimethylamphetamine (BEATRICE), 2,5-bis(methylthio)-4-methylamphetamine (BIS-TOM), 4-bromo-2,5,β-trimethoxyphenethylamine (BOB), 2,5,β-trimethoxy-4-methylphenethylamine (BOD), β-methoxy-3,4-methylenedioxyphenethylamine (BOH), 2,5-dimethoxy-β-hydroxy-4-methylphenethylamine (BOHD), 3,4,5,β-tetramethoxyphenethylamine (BOM), 4-bromo-3,5-dimethoxyamphetamine (4-Br-3,5-DMA), 2-bromo-4,5-methylenedioxyamphetamine (2-Br-4,5-MDA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-benzyloxy-3,5-dimethoxy-amphetamine (3C-BZ), 4-chloro-2,5-dimethoxyphenethylamine (2C-C), 2,5-dimethoxy-4-methyl-phenethylamine (2C-D), 2,5-dimethoxy-4-ethyl-phenethylamine (2C-E), 3,5-dimethoxy-4-ethoxyamphetamine (3C-E), 2,5-dimethoxy-4-fluorophenethylamine (2C-F), 2,5-dimethoxy-3,4-dimethylphenethylamine (2C-G), 2,5-dimethoxy-3,4-trimethylene-phenethylamine (2C-G-3), 2,5-Dimethoxy-3,4-tetramethylenephenethylamine (2C-G-4), 3,4-Norbornyl-2,5-dimethoxyphenethylamine (2C-G-5), 1,4-Dimethoxynaphthyl-2-ethylamine (2C-G-N), 2,5-Dimethoxyphenethylamine (2C-H), 4-Iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-Dimethoxy-4-nitro-phenethylamine (2C-N), 2,5-Dimethoxy-4-isopropoxyphenethylamine (2C-O-4), 2,5-Dimethoxy-4-propylphenethylamine (2C-P), 4-Cyclopropylmethoxy-3,5-dimethoxyphenethylamine (CPM), 2,5-Dimethoxy-4-methylselenophenethylamine (2C-SE), 2,5-Dimethoxy-4-methylthiophenethylamine (2C-T), 2,5-Dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-Dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,6-Dimethoxy-4-isopropylthiophenethylamine (psi-2C-T-4), 2,5-Dimethoxy-4-propylthiophenethylamine (2C-T-7), 4-Cyclopropylmethylthio-2,5-dimethoxyphenethylamine (2C-T-8), 4-(t)-Butylthio-2,5-dimethoxy-phenethylamine (2C-T-9), 2,5-Dimethoxy-4-(2-methoxyethylthio)phenethylamine (2C-T-13), 4-Cyclopropylthio-2,5-dimethoxyphenethylamine (2C-T-15), 4-(s)-Butylthio-2,5-dimethoxyphenethylamine (2C-T-17), 2,5-Dimethoxy-4-(2-fluoroethylthio)phenethylamine (2C-T-21), 3,5-Dimethoxy-4-trideuteriomethylphenethylamine (4-D), β,β-Dideutero-3,4,5-trimethoxyphenethylamine (β-D), 3,5-Dimethoxy-4-methyl-phenethylamine (DESOXY), 2,4-Dimethoxyanfetamine (2,4-DMA), 2,5-Dimethoxyanfetamine (2,5-DMA), 3,4-Dimethoxyanfetamine (3,4-DMA), 2-(2,5-Dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA), 3,4-Dimethoxy-β-hydroxyphenethylamine (DME), 2,5-dimethoxy-3,4-methylenedioxyamphetamine (DMMDA), 2,3-dimethoxy-4,5-methylenedioxyamphetamine (DMMDA-2), 3,4-dimethoxyphenethylamine (DMPEA), 4-amyl-2,5-dimethoxyamphetamine (DOAM), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-butyl-2,5-dimethoxyamphetamine (DOBU), 4-chloro-2,5-dimethoxyamphetamine (DOC), 2,5-dimethoxy-4-(2-fluoroethyl)amphetamine (DOEF), 2,5-dimethoxy-4-ethylamphetamine (DOET), 4-iodo-2,5-dimethoxyamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM(STP)), 2,6-dimethoxy-4-methylamphetamine (psi-DOM), 2,5-dimethoxy-4-nitroamphetamine (DON), 2,5-dimethoxy-4-propylamphetamine (DOPR), 3,5-dimethoxy-4-ethoxyphenethylamine (E), 2,4,5-triethoxyamphetamine (EEE), 2,4-diethoxy-5-methoxyamphetamine (EEM), 2,5-diethoxy-4-methoxyamphetamine (EME), 4,5-dimethoxy-2-ethoxyamphetamine (EMM), 2-ethylamino-1-(3,4-methylenedioxyphenyl)butane (ETHYL-J), 2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane (ETHYL-K), 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran (F-2), 6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran (F-22), N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine (FLEA), 2,5-dimethoxy-3,4-(trimethylene)amphetamine (G-3), 2,5-dimethoxy-3,4-(tetramethylene)amphetamine (G-4), 3,6-dimethoxy-4-(2-aminopropyl)benzobornane (G-5), 2,5-dimethoxy-3,4-dimethyl-amphetamine (GANESHA), 1,4-Dimethoxynaphthyl-2-isopropylamine (G-N), 2,5-Dimethoxy-4-ethylthio-N-hydroxyphenethylamine (HOT-2), 2,5-Dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine (HOT-7), 4-(s)-Butylthio-2,5-dimethoxy-N-hydroxyphenethylamine (HOT-17), 2,5-Dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA), 2,3,4-Trimethoxy-phenethylamine (IM), 3,5-Dimethoxy-4-isopropoxyphenethylamine (IP), 5-Ethoxy-2-methoxy-4-methylamphetamine (IRIS), 2-Amino-1-(3,4-methylenedioxyphenyl)butane (J, BDB), 3-Methoxy-4,5-methylenedioxyphenethylamine (LOPHOPHINE), 3,4,5-Trimethoxy-phenethylamine (M), 4-Methoxyamphetamine (4-MA, PMA), 2,N-Dimethyl-4,5-methylenedioxyamphetamine (MADAM-6), 3,5-Dimethoxy-4-methallyloxyphenethylamine (MAL), 3,4-Methylenedioxyamphetamine (MDA), N-Allyl-3,4-methylenedioxyamphetamine (MDAL), N-Butyl-3,4-methylenedioxyamphetamine (MDBU), N-Benzyl-3,4-methylenedioxy-amphetamine (MDBZ), N-Cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM), N,N-Dimethyl-3,4-methylenedioxyamphetamine (MDDM), N-Ethyl-3,4-methylenedioxy-amphetamine (MDE), N-(2-Hydroxyethyl)-3,4-methylenedioxyamphetamine (MDHOET), N-Isopropyl-3,4-methylenedioxyamphetamine (MDIP), N-Methyl-3,4-methylenedioxy-amphetamine (MDMA), 3,4-Ethylenedioxy-N-methylamphetamine (MDMC), N-Methoxy-3,4-methylenedioxyamphetamine (MDMEO), N-(2-Methoxyethyl)-3,4-methylenedioxyamphetamine (MDMEOET), 3,4-Methylenedioxy-α,α,N-trimethylphenethylamine (MDMP), N-Hydroxy-3,4-Methylenedioxyamphetamine (MDOH), 3,4-methylenedioxyphenethylamine (MDPEA), α,α-dimethyl-3,4-methylenedioxyphenethylamine (MDPH), 3,4-methylenedioxy-N-propargyl-amphetamine (MDPL), 3,4-methylenedioxy-N-propyl-amphetamine (MDPR), 3,4-dimethoxy-5-ethoxyphenethylamine (ME), 4,5-ethylenedioxy-3-methoxyamphetamine (MEDA), 4,5-diethoxy-2-methoxyamphetamine (MEE), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), 4-ethoxy-3-methoxyphenethylamine (MEPEA), 5-bromo-2,4-dimethoxyamphetamine (META-DOB), 2,4-dimethoxy-5-methylthioamphetamine (META-DOT), 2,5-dimethoxy-N-methylamphetamine (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methylamphetamine (METHYL-DOB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (METHYL-J, MBDB), 2-methylamino-1-(3,4-methylenedioxyphenyl)pentane (METHYL-K), 4-methoxy-N-methyl-amphetamine (METHYL-MA, PMMA), 2-methoxy-N-methyl-4,5-methylenedioxyamphetamine (METHYL-MMDA-2), 3-methoxy-4,5-methylenedioxyamphetamine (MMDA), 2-methoxy-4,5-methylenedioxyamphetamine (MMDA-2), 2-methoxy-3,4-methylenedioxyamphetamine (MMDA-3a), 4-methoxy-2,3-methylenedioxyamphetamine (MMDA-3b), 2,4-dimethoxy-5-ethoxyamphetamine (MME), 3,4-dimethoxy-5-(n)-propoxyphenethylamine (MP), 2,5-dimethoxy-4-(n)-propoxyamphetamine (MPM), 4,5-dimethoxy-2-methylthioamphetamine (ORTHO-DOT), 3,5-dimethoxy-4-propoxyphenethylamine (P), 3,5-dimethoxy-4-phenethyloxyphenethylamine (PE), phenethylamine (PEA), 3,5-Dimethoxy-4-(2-propynyloxy)phenethylamine (PROPYNYL), 3,5-diethoxy-4-methoxyphenethylamine (SB), 2,3,4,5-tetramethoxyanfetamine (TA), 4-ethoxy-3-ethylthio-5-methoxyphenethylamine (3-TASB), 3-ethoxy-4-ethylthio-5-methoxyphenethylamine (4-TASB), 3,4-diethoxy-5-methylthio-phenethylamine (5-TASB),, 4-(n)-butylthio-3,5-dimethoxyphenethylamine (TB), 4-ethoxy-5-methoxy-3-methylthiophenethylamine (3-TE), 3,5-dimethoxy-4-ethylthiophenethylamine (TE, 4-TE), 3,4-dimethoxy-2-methylthiophenethylamine (2-TIM), 2,4-dimethoxy-3-methylthio-phenethylamine (3-TIM), 2,3-dimethoxy-4-methylthiophenethylamine (4-TIM), 3,4-dimethoxy-5-methylthiophenethylamine (3-TM), 3,5-dimethoxy-4-methylthiophenethylamine (4-TM), 3,4,5-trimethoxyanfetamine (TMA), 2,4,5-trimethoxyanfetamine (TMA-2), 2,3,4-trimethoxyanfetamine (TMA-3), 2,3,5-trimethoxyanfetamine (TMA-4), 2,3,6-trimethoxyanfetamine (TMA-5), 2,4,6-trimethoxyanfetamine (TMA-6), 4,5-dimethoxy-3-ethylthiophenethylamine (3-TME), 3-ethoxy-5-methoxy-4-methylthio-phenethylamine (4-TME), 3-ethoxy-4-methoxy-5-methylthiophenethylamine (5-TME), 3,4-methylenedioxy-2-methylthioanfetamine (2T-MMDA-3a), 2-methoxy-4,5-methylenedithioxyanfetamine (4T-MMDA-2), 2,4,5-trimethoxyphenethylamine (TMPEA), 4-ethyl-5-methoxy-2-methylthioanfetamine (2-TOET), 4-ethyl-2-methoxy-5-methylthioanfetamine (5-TOET), 5-methoxy-4-methyl-2-methylthioanfetamine (2-TOM), 2-methoxy-4-methyl-5-methylthioanfetamine (5-TOM), 2-methoxy-4-methyl-5-methyl-sulfinylanfetamine (TOMSO), 3,5-dimethoxy-4-propylthiophenethylamine (TP), 3,4,5-triethoxyphenethylamine (TRIS), 3-ethoxy-5-ethylthio-4-methoxyphenethylamine (3-TSB), 3,5-diethoxy-4-methylthiophenethylamine (4-TSB), 3,4-diethoxy-5-ethylthio-phenethylamine (3-T-TRIS), 3,A phenethylamine selected from the group consisting of 5 - diethoxy - 4 - ethylthiophenethylamine (4 - T - TRIS), (R)-2,5 - dimethoxy - 4 - iodoamphetamine (R - DOI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, or a combination thereof.,

[0179] In some embodiments, the additional active compound is an ergot alkaloid. In some embodiments, the additional active compound is an ergoline. In some embodiments, the additional active compound is a lysergamide. As will be understood by those skilled in the art, lysergamide is a compound having the following general structure, where R N1 R N2 R 1 R 2 R 4 R 6 R 7 R 8 R 9 R 12 R 13 and R 14 are as defined herein and as generally understood in the art:

Chemical formula

[0180] In some embodiments, R N1 R N2 R 1 R 2 R 4 R 6 R 7 R 8 R 9 R 12 R 13 and R 14is, independently of one another, hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Further, R N1 、R N2 、R 1 、R 2 、R 4 、R 6 、R 7 、R 8 、R 9 、R 12 、R 13 、and R 14 any two of which and intervening atoms together can form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In some embodiments, the reserlgamide is a quaternary salt in which an additional R 6A is attached to the nitrogen to which R 6 is attached; R 6A is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0181] In some embodiments, the additional active compound is a lysergamide selected from the group consisting of diethylamide lysergate (i.e., LSD, LSD-25, LAD, Delysid), 6-ethyl-6-nor-lysergic acid diethylamide (ETH-LAD), 6-propynyl-6-nor-lysergic acid diethylamide (PARGY-LAD), 6-allyl-6-nor-lysergic acid diethylamide (AL-LAD), 6-propyl-6-nor-lysergic acid diethylamide (PRO-LAD), 6-isopropyl-6-nor-lysergic acid diethylamide (IP-LAD), 6-cyclopropyl-6-nor-lysergic acid diethylamide (CIP-LAD), 6-butyl-6-nor-lysergic acid diethylamide (BU-LAD), 6-(2-fluoroethyl)-6-nor-lysergic acid diethylamide (FLUOROETH-LAD), 1-acetyl-lysergic acid diethylamide (i.e., ALD, ALD-52, N-acetyl-LSD), 1-propionyl-lysergic acid diethylamide (1P-LSD), 1-butyryl-lysergic acid diethylamide (1B-LSD), 1-valeryl-lysergic acid diethylamide (1V-LSD), 1-(cyclopropyl-methanoyl)-lysergic acid diethylamide (1cP-LSD), 1-(1,2-dimethylcyclobutane-1-carbonyl)-lysergic acid diethylamide (1D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1P-AL-LAD), 1-(cyclopropylmethanoyl)-6-allyl-6-nor-lysergic acid diethylamide (1cP-AL-LAD), 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), lysergic acid 2,4-dimethylazetide (i.e., LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), and methylisopropylamide lysergate (MIPLA).

[0182] Other tryptamines, phenethylamines, and lysergamides that are useful as further active compounds for the purposes of the present invention and are therefore contemplated to be included therein are generally known in the art (see, for example, Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob&Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi&Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacological Reviews, 2016; 68(2), 264-355; Glennon, Pharmacology Biochemistry and Behavior, 1999; 64, 251-256; each of which is incorporated by reference as if fully set forth herein).

[0183] E. Dosage and Administration In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount or an effective amount of the disclosed compound for administration to a subject, etc. Administration of a "therapeutically effective amount" or "effective amount" of the pharmaceutical composition to a subject means administration of an amount of the composition sufficient to achieve the desired effect. When an "effective amount" means an amount effective to treat a disorder or condition described in a subject, a "therapeutic effect" is understood to mean the response(s) in a mammal after treatment that are determined to be desirable and beneficial. Thus, depending on the mental health disorder being treated, or the desired mental health or functional improvement sought, and depending on the specific component(s) in the disclosed composition under consideration, those responses will vary, but will be readily understood by one of ordinary skill in the art through the disclosure herein and understanding of the general knowledge in the art (e.g., by reference to the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for the disorder described).

[0184] In some embodiments, when the pharmaceutical composition comprises the disclosed compound, it may be present in an amount such that the single dose is (in milligram dosage calculated based on the patient's kilogram body weight), for example, 0.25 mg / kg or less (including dosages of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, and in amounts within these ranges.

[0185] In some embodiments, when the pharmaceutical composition contains the disclosed compound, it may be present in an amount such that the single dose (calculated in milligrams per kilogram of the patient's body weight) is from about 0.01 mg / kg to 0.1 mg / kg, for example about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, and about 0.1 mg / kg, and ranges between these values. In some embodiments, the single dose is from about 0.1 mg / kg to 1.0 mg / kg, for example about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, and about 1.0 mg / kg, and ranges between these values.

[0186] In some embodiments, when the pharmaceutical composition contains the disclosed compound, it may be present in an amount such that the single dose (regardless of whether such a dose is present in a unit dosage form) is, for example, 25 mg or less (including 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, and amounts within these ranges.

[0187] In some embodiments, when a pharmaceutical composition comprises the disclosed compounds, it may be present in an amount such that the single dose is from about 0.1 mg to 1.0 mg (regardless of whether such a dose is present in a unit dosage form), for example about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, and ranges between these values. In embodiments, the single dose is from about 1 mg to 10 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, and ranges between these values. In some embodiments, the single dose is from about 10 mg to 100 mg.

[0188] In some embodiments, when the pharmaceutical composition contains a further active compound, for example when the further active compound is phenethylamine or another tryptamine, it is present in an amount such that the single dose is (in milligram dose calculated based on the patient's kilogram body weight), for example, 0.25 mg / kg or less (including doses of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, and can be present in amounts within these ranges.

[0189] In some embodiments, when the pharmaceutical composition comprises a further active compound, for example when the further active compound is phenethylamine or tryptamine, the single dose (regardless of whether such a dose is present in a unit dosage form) is, for example, 25 mg or less (including 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, and may be present in an amount such as amounts within these ranges.

[0190] It will be readily understood that the dosage may vary depending on whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability or susceptibility of the symptoms being treated, the desired clinical endpoint, previous, concurrent or subsequent treatments, the general health, age, sex and race of the subject, bioavailability, the potential for systemic, local or topical adverse side effects, the presence of other disorders or diseases in the subject, and other factors understood by those of skill in the art (e.g., medical history or family history).

[0191] The dosage, frequency, or duration can be increased or decreased as desired clinical outcome, disease state or symptom condition, any adverse side effects of treatment or therapy, or as indicated by co-administered drugs. Those skilled in the art having the teachings of the present disclosure at hand will understand the factors that can affect the dosage, frequency, and timing necessary to provide an amount sufficient or effective to provide a therapeutic effect or benefit, and to do so according to the type of desired therapeutic effect, and to avoid or minimize adverse effects.

[0192] In some embodiments, the dosage actually administered is determined by the physician in light of the disorder being treated, the selected route of administration, the actual composition or formulation being administered, the age, weight and response of the individual patient, and the relevant circumstances including the severity of the patient's symptoms, and thus it will be understood that none of the dosage ranges disclosed herein are intended to limit the scope of the invention. In some instances, dosage levels below the lower limit of the disclosed range may be sufficient or more than sufficient, while in other instances, dosages above the range may be used without causing adverse side effects, for example, such larger dosages may also be divided into several smaller dosages for administration, taken together or separately.

[0193] In some embodiments, particularly when the formulation is prepared in a single unit dosage form such as a capsule, tablet, or lozenge, the recommended dosage will be known by reference to the form of the formulation itself. In other embodiments, when the formulation is prepared in multiple dosage forms, such as a liquid suspension and a topical formulation, the recommended dosage may be known by reference to the means of administration, or by reference to the packaging and labeling, package insert, marketing materials, training materials, or other information and knowledge available to those skilled in the art or to the public.

[0194] Accordingly, another aspect of the present disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the present invention, recommended dosing guidelines or prescription information therefor, and a suitable container. The individual unit dosage forms may be included in a multi-dose kit or container. The pharmaceutical formulation can also be packaged in single or multiple unit dosage forms for dosage uniformity and ease of administration.

[0195] F. Kit Another aspect of the present disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the present invention, recommended dosing guidelines or prescription information therefor, and a suitable container. The individual unit dosage forms may be included in a multi-dose kit or container. The pharmaceutical formulation can also be packaged in single or multiple unit dosage forms for dosage uniformity and ease of administration.

[0196] The kit generally includes suitable packaging. The kit can include one or more containers containing any of the compounds described herein. Each component (if there are two or more components) can be packaged in a separate container or some components can be combined in one container where cross-reactivity and shelf life permit. The kit can be in unit dosage form, bulk package (e.g., multi-dose package) or sub-unit dosage. For example, a kit can be provided that contains a sufficient dosage of the compounds disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein to provide effective treatment of an individual over any of a number of extended periods such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. The kit may also include multiple unit dosages of the compound and instructions for use and can be packaged in an amount sufficient for storage and use in a pharmacy (e.g., hospital pharmacy and dispensing pharmacy).

[0197] Preferably, information regarding dosing and appropriate administration (if necessary) is printed directly on the multiple-dose kit (e.g., on the blister pack or other inner packaging holding the composition or formulation of the present invention); however, the kits of the present invention can further include package inserts and other printed instructions (e.g., on the outer package) for administering the disclosed compositions and for their appropriate therapeutic use.

[0198] G. Method of Use In some aspects, methods of using the disclosed compounds are provided herein. In some embodiments, the disclosed compounds are used to modulate neurotransmission. In embodiments, the disclosed compounds are used to treat a condition such as a disease or disorder. In embodiments, the disclosed compounds are used in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a condition such as a disease or disorder. In embodiments, the disclosed compounds are administered as part of a treatment. In embodiments, the disclosed compounds are administered in combination with psychotherapy, psychological support, or patient monitoring. In embodiments, the disclosed compounds are administered in a therapeutically effective amount to a subject having a condition such as a disease or disorder. In some embodiments, the condition is a mental health disorder. In some embodiments, the condition is a neurodegenerative disorder. In embodiments, the condition is an inflammatory disorder. In embodiments, the condition is pain and / or inflammation. In embodiments, the disclosed compounds are administered to a healthy subject.

[0199] As used herein, the terms "subject," "user," "patient," and "individual" are used interchangeably and refer to any mammal, including mice, monkeys, mammalian livestock, mammalian sport animals, and mammalian pets such as dogs and cats, but preferably refer to humans. Such terms are understood to include those having an indication for which the compounds, compositions, or methods described herein may be effective, or otherwise those who may benefit from the present invention. In general, all of the compounds, compositions, and disclosed methods are understood to function for all individuals, although the diversity of individuals should be expected and will be understood. The disclosed methods of treatment can also be modified to treat multiple patients, including couples or families, at one time. Accordingly, these terms are also understood to mean two or more individuals.

[0200] In some embodiments, the disclosed compounds or compositions thereof are administered to a subject orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, or transdermally. In embodiments, when administered via one or more such routes, the disclosed compounds and the disclosed compositions and formulations containing them are useful in methods of treating patients in need of such treatment.

[0201] a. Research tool In some aspects, the disclosed compounds are used as research tools involved in determining the structure and function of receptors, for example, in vitro, in vivo, or in silico. In embodiments, the disclosed compounds can be used in receptor, ion channel, enzyme, and transporter binding studies. In embodiments, the disclosed compounds can be used in mapping and functional studies.

[0202] In embodiments, radiolabeled disclosed compounds can be used to identify binding sites. In embodiments, radiolabeled disclosed compounds can be used for tissue imaging.

[0203] In some embodiments, the disclosed compounds can be used as research tools for 5-HT2 receptors. In embodiments, the disclosed compounds can be used as research tools for 5-HT 2A receptors. In embodiments, the disclosed compounds can be used as research tools for 5-HT 2B receptors. In embodiments, the disclosed compounds can be used as research tools for 5-HT 2C receptors. In embodiments, the research tools can be receptor probes that can be used to determine events downstream of receptor-ligand interactions, such as calcium regulation, kinase, phosphatase, and phospholipase activation, and lipid transport. In embodiments, the receptor is a recombinant receptor. In embodiments, the receptor is a wild-type receptor.

[0204] In some embodiments, the disclosed compounds can be used as research tools such as receptor probes for 5-HT2 receptors of mammalian origin. In embodiments, the disclosed compounds can be used as research tools such as receptor probes for 5-HT2 receptors of human (Homo sapiens) origin. In embodiments, the disclosed compounds can be used as research tools such as receptor probes for 5-HT2 receptors of non-human primate origin. Non-limiting examples of non-human primate 5-HT2 receptors include the chimpanzee (Pan troglodytes) and rhesus monkey (Macaca mulatta) 5-HT2 receptors.

[0205] In some embodiments, the disclosed compounds can be used as research tools such as receptor probes for rodent - derived 5 - HT2 receptors. Non - limiting examples of rodent 5 - HT2 receptors include those derived from mice (Mus musculus) and rats (Rattus norvegicus). Common laboratory mouse strains include C57BL / 6 and BALB / c, and common laboratory rat strains include Sprague - Dawley and Wistar. In embodiments, the disclosed compounds can be used as research tools such as receptor probes for zebrafish - derived 5 - HT2 receptors. Non - limiting examples of zebrafish 5 - HT2 receptors include those derived from the Danio species, such as Danio rerio. In embodiments, the disclosed compounds can be used as research tools such as receptor probes for nematode - derived 5 - HT2 receptors. In one non - limiting example, the 5 - HT2 receptor of Caenorhabditis elegans can be probed with the disclosed compounds. In embodiments, the disclosed compounds can be used as research tools such as receptor probes for dog, chicken, frog or bovine 5 - HT2 receptors.

[0206] Sequences can be retrieved by searching nucleotide databases such as Genbank or amino acid databases such as UniProtKB, as known to those of skill in the art. By way of example, the sequences 1 - 45 in Table 5 are available in UniProtKB (www.uniprot.org) by reference to their respective accession numbers below; they are also disclosed in the priority documents of this specification, which are incorporated as if fully set forth herein.

Table 7 - 1

Table 7 - 2

Table 7-3

[0207] b. Serotonin receptor ligand The 5-HT receptor system contains 14 different receptors that are classified into 7 receptor families (5-HT1-5-HT7). Except for the 5-HT3 ligand-gated ion channel, all 5-HTR families are G protein-coupled receptors (GPCRs) (Gothert, Pharmacol Rep., 2013;65(4):771-86). In one representative example, the 5-HT 2A receptor, like other GPCRs, has 7 transmembrane helices and an intracellular amphipathic helix H8. The receptor contains, in addition to the accessory site, a ligand-binding site called the orthosteric site and a side-extended cavity that connects the orthosteric site to the plasma membrane. In this specification, the side-extended cavity may sometimes be referred to herein as the "extended binding site" or "exosite".

[0208] In some embodiments, the disclosed compounds bind to serotonin (5-HT) receptors. In an embodiment, the 5-HT receptor is a subtype 1 (5-HT1) receptor. In an embodiment, the 5-HT receptor is a subtype 2 (5-HT2) receptor. In an embodiment, the 5-HT2 receptor is a subtype 2A, 2B or 2C (5-HT 2A , 5-HT 2B or 5-HT 2C ) receptor. In an embodiment, the 5-HT receptor is a subtype 4 (5-HT4) receptor. In an embodiment, the receptor is a 5-HT receptor of the subtype 5 (5-HT5) receptor. In an embodiment, the receptor is a 5-HT receptor of the subtype 6 (5-HT6) receptor. In an embodiment, the 5-HT receptor is a subtype 7 (5-HT7) receptor. In an embodiment, the receptor is of mammalian origin. In an embodiment, the receptor is of human origin. In an embodiment, the receptor is recombinant.

[0209] In some embodiments, the disclosed compounds bind to serotonin (5-HT) receptors at two or more sites such as orthosteric sites and extended binding sites. In embodiments, the disclosed compounds bind to 5-HT1 receptors at one or more sites such as orthosteric sites and extended binding sites. In embodiments, the disclosed compounds bind to 5-HT2 receptors at one or more sites such as orthosteric sites and extended binding sites. In embodiments, the disclosed compounds bind to one or more sites such as orthosteric sites and extended binding sites, 5-HT 2A 、5-HT 2B and 5-HT 2C and one or more 5-HT2 receptor subtypes such as receptors. In embodiments, the disclosed compounds bind to 5-HT4 receptors at one or more sites such as orthosteric sites and extended binding sites. In embodiments, the disclosed compounds bind to 5-HT5 receptors at one or more sites such as orthosteric sites and extended binding sites. In embodiments, the disclosed compounds bind to 5-HT6 receptors at one or more sites such as orthosteric sites and extended binding sites. In embodiments, the disclosed compounds bind to 5-HT7 receptors at one or more sites such as orthosteric sites and extended binding sites. In embodiments, the receptors are of mammalian origin. In embodiments, the receptors are of human origin. In embodiments, the receptors are recombinant.

[0210] As determined in the complex with the antagonist zotepine, the extended binding site extends over transmembrane domains (TMDs) 4 and 5 and is surrounded by hydrophobic residues on TMD3, TMD4, TMD5 and extracellular loop (ECL) 2. The glycine residue at position 5.42x43 at the entrance of the lateral extended cavity is essential for the formation of the exosite. This glycine position is conserved only in receptors of the 5-HT2 family (Kimura et al., Nat Struct Mol Biol., 2019;26(2):121-128). The extended binding site is 5-HT 1B and 5-HT 2BReceptors are also described (McCorvy & Roth, Pharmacology & Therapeutics, 2015; 150: 129-142).

[0211] For example, methods for determining binding to 5-HT receptors, including in vitro and in silico computational methods, are available to those skilled in the art. For example, Kimura et al. constructed 5-HT 2A R, crystallized the receptor using inverse agonists and antagonists, and determined the binding using microcrystallography and the molecular docking software Glide (Schrodinger) (Kimura et al., Nature Structural & Molecular Biology, 2019; 26: 121-128). Wacker et al. described using X-ray crystallography to elucidate the structure of LSD bound to engineered 5-HT 2B receptors. Considering the homology between 5-HT 2A receptors and 5-HT 2B receptors, 5-HT 2B receptors were used as a model system for 5-HT 2A receptors (Wacker et al., Cell. 2017; 168(3): 377-389.e12). X-ray crystallography has also been used to determine the structure of 5-HT 2A R complexed with LSD and the inverse agonist methiothepin, but cryo-electron microscopy of the prototypical hallucinogen 25CN-NBOH complexed with engineered Gαq heterotrimers has been used to determine the active state of 5-HT 2A R (Kim et al., Cell. 2020 Sep 17; 182(6): 1574-1588.e19). Homology modeling based on the β(2)-adrenergic receptor and G protein-coupled opsin crystal structures has also been used to model 5-HT 2A R (Isberg et al., J Chem Inf Model., 2011; 51(2): 315-25).

[0212] Furthermore, similar strategies used to elucidate the ADRB2 exosite, such as docking studies and mutagenicity studies, can be applied to the 5-HT receptor. For example, site-directed mutagenesis and evaluation of salmeterol-stimulated cAMP accumulation identified that amino acids (residues 149 - 174) in TMD4 contribute to the β2 receptor exosite (Green et al., J Biol Chem., 1996; 271(39):24029 - 35). 125 I] Direct photoaffinity labeling of the salmeterol binding site of the human β2 receptor with iodoazidosalmeterol, as well as X-ray diffraction analysis of salmeterol bound to ADRB2, revealed that TMD6 and TMD7 also contribute to the exosite (Masureel et al., Nat.Chem.Biol.2018;14(11):1059 - 1066; Rong et al., Biochemistry, 1999; 38(35):11278 - 11286). 125 I] In the photo-labeling study of iodoazidosalmeterol, the radioiodinated phenylazide moiety of the photoaffinity probe corresponding to the terminal phenyl ring of salmeterol specifically bound to tryptophan 313 in TMD7 (Rong et al., Biochemistry, 1999; 38(35):11278 - 11286). A third study using chimeric β1 / β2 receptor and alanine-substituted β2 receptor mutants also identified TMD7 as part of the exosite. In this study, tyrosine 308 and tyrosine 316 in TMD7 were identified as sites of interaction with the protonated amine of salmeterol and the methylene group near the side-chain ether oxygen of salmeterol, respectively (Isogaya et al., Mol.Pharmacol.1998; 54:616 - 622).

[0213] 5-HT 2ABoth the R and ADRB2 receptors adopt various conformations in response to different ligands. This movement and the resulting remodeling of the surrounding membrane affect the known pharmacological activities of ligands such as full, partial or inverse agonists of the receptor. For example, Shan et al. showed different 5-HT 2A R conformations in response to the partial agonist LSD and the inverse agonist ketanserin (Shan et al., PLoS Comput Biol. 2012;8(4):e1002473). In the context of ADRB2 ligand research, most of the receptor residues showed different reactivity patterns even between functionally similar ligands, and there were few receptor residues with reactivity patterns consistent with classical agonism (Kahsai et al., Nat Chem Biol. 2011;7(10):692-700). The various conformational states of the 5-HT receptor can lead to different pharmacological outcomes, including those related to hallucination generation. See, for example, Weinsten, AAPS J 7:E871-884. Thus, in one aspect, the provided 5-HT receptor ligands can be useful for elucidating the structural basis and mechanisms for various states of 5-HT receptor activation, such as 5-HT 2A R, 5-HT 2B R and 5-HT 2C R.

[0214] In some embodiments, the disclosed compounds have increased binding affinity for the 5-HT receptor compared to a comparator. In embodiments, the disclosed compounds have decreased binding affinity for the 5-HT receptor compared to a comparator. In embodiments, the disclosed compounds have both increased binding affinity for a 5-HT receptor subtype and decreased binding affinity for another serotonin receptor subtype. In embodiments, the receptor is a 5-HT 2A receptor. In embodiments, the receptor is a 5-HT 2B receptor. In embodiments, the receptor is a 5-HT 2CIt is a receptor. In one example, the disclosed compounds, such as N-substituted 2C-B (e.g., XOB; see Examples 1 and 2), have an increased affinity for the 5-HT2 receptor compared to a comparator. In embodiments, the comparator is the corresponding unsubstituted phenylalkylamine. For example, in embodiments, the comparator of XOB is 2C-B. In other embodiments, the comparator is serotonin.

[0215] In some embodiments, the disclosed compounds have an increased selectivity or specificity for the 5-HT receptor compared to a comparator. In embodiments, the disclosed compounds have a relatively high selectivity for the 5-HT2 receptor, such as 5-HT 2A 、5-HT 2B 、and 5-HT 2C receptors compared to a comparator. In embodiments, the comparator is an unsubstituted phenylalkylamine, including, for example, compounds having the same phenylalkylamine head group but lacking a side chain. In embodiments, the disclosed compounds have fewer off-target effects, including, for example, adverse effects.

[0216] Various strategies are available for determining binding affinity and specificity. In particular, the results of binding assays represent the strength of the interaction between a ligand and a target, rather than whether the ligand acts as an agonist or antagonist. Radioligand binding experiments are sensitive and quantitative techniques for determining the binding affinity between a compound and a receptor. The general framework of a radioligand binding assay involves preparing tissue with the target receptor and incubating it with a radiolabeled ligand until equilibrium is reached. The equilibrium is then disrupted, and the radiolabeled ligand bound to the receptor and the free radioligand are separated, and the radioactivity, such as the radioactivity bound to the tissue, is quantified and the results are analyzed using, for example, dedicated computer software. Under the same conditions, nonspecific binding is measured by incubating the tissue in the presence of an unlabeled ligand at a concentration that saturates the target receptor. Specific binding is calculated by subtracting nonspecific binding from total binding.

[0217] The use of radioligands can assist in several different experimental situations, including rate experiments where the time course of ligand association and dissociation is determined, competitive binding assays, dissociation binding assays, saturation binding assays, as well as the determination of binding affinity in quantitative autoradiography and image analysis (Maguire et al., Methods Mol Biol. 2012;897:31-77).

[0218] In some embodiments, affinity can be evaluated by determining the inhibition constant of receptors such as N-aralkyloxyalkyl-substituted phenylalkylamines and 5-HT2 receptors. The inhibition constant (K i ) can be expressed as the concentration at which 50% of the radiolabeled ligand, such as an agonist, is displaced by the test ligand. Thus, as shown by the Cheng-Prusoff equation, K 50 can be determined using the observed IC i , where K i = IC 50 / (1 + [R] / K d ), IC 50 is the concentration of the competitive inhibitor that results in 50% inhibition, R is the concentration of the radioligand used in the competitive binding assay, and K d is the equilibrium dissociation constant of the radioligand in the assay.

[0219] K i can be determined using a competitive binding assay, also referred to as a radioligand displacement assay. Generally, the effect of the test ligand on the interaction between the radiolabeled ligand and the receptor preparation is evaluated, for example, the degree of radiolabeled ligand displacement is evaluated.

[0220] In some examples, the radioligand being displaced can be an antagonist, such as 2A H] ketanserin for 5-HT 3 , 2C H] methysergide for 5-HT 3 . In some examples, the radioligand being displaced can be an agonist, such as 5-HT2B Regarding 3 it may be H]LSD. However, antagonist substitution may reflect binding to both active and inactive receptor conformations, while agonist substitution probably reflects binding to the active conformation, so consistency in test conditions is preferred for comparison (Toro-Sazo et al., PLoS One, 2019;14(1):e0209804). Binding assays are further described, for example, in Roth’s National Institutes of Mental Health Psychoactive Drug Screening Program, Assay Protocol Book, Version III, 2018.

[0221] In some embodiments, the disclosed compounds have a binding affinity of less than 10 μM, less than 5 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM for any one or more of 5-HT 2A 5-HT 2B and 5-HT 2A In embodiments, the disclosed compounds have a binding affinity of about 10 μM, 5 μM, 1 μM, 0.5 μM, or 0.1 μM for any one or more of 5-HT 2A 5-HT 2B and 5-HT 2A In embodiments, the disclosed compounds have an increased binding affinity for any one or more of 5-HT 2A 5-HT 2B and 5-HT 2A compared to a comparator. In embodiments, the disclosed compounds have a decreased binding affinity for any one or more of 5-HT 2A 5-HT 2B and 5-HT 2A compared to a comparator. In embodiments, the comparator is serotonin. In embodiments, the comparator is the corresponding unsubstituted phenylalkylamine. In embodiments, the comparator of XOB is 2C-B. For example, XOB has a binding affinity for 5-HT 2A of 2.6 μM (see Example 2), for 5-HT1A has no measurable affinity. In comparison, in heterologous cells expressing human or rat 5-HT 2A receptors, in vitro tests using 125 I]-DOI competitive binding reported high affinity for 2C-B at 0.88 nM and 0.66 nM, respectively (McLean et al., J Med Chem., 2006;49(19):5794-5803). Furthermore, serotonin showed moderate K I values of 330 nM, 470 nM, and 120 nM at the 5-HT 1A , 5-HT 2A、 and 5-HT 2C receptors, respectively. In embodiments, the binding affinity of the disclosed compounds for any one or more of 5-HT I , 5-HT 2A , 5-HT 2B , and 5-HT 2A is increased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 500-fold, 1000-fold or at least 1000-fold compared to the comparator. In embodiments, the binding affinity of the disclosed compounds for any one or more of 5-HT 2A , 5-HT 2B and 5-HT 2A is decreased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 500-fold, 1000-fold or at least 1000-fold compared to the comparator.

[0222] In some embodiments, the disclosed compounds have higher selectivity for the 5-HT 2B receptor than for another serotonin receptor (e.g., the 5-HT 2C receptor and / or the 5-HT 2A receptor), compared to the comparator. In embodiments, the disclosed compounds have higher selectivity for the 5-HT 2B receptor than for the 5-HT 2A receptor, compared to the comparator. In embodiments, the disclosed compounds have higher selectivity for the 5-HT 2C receptor than for the 5-HT 2AIt has high selectivity for the receptor. In embodiments, the disclosed compounds, compared to a comparator, are 5-HT 2B receptor and 5-HT 2C receptor, are more selective for the 5-HT 2A receptor.

[0223] In some embodiments, the selectivity is defined by the ratio of the maximum half-maximal effective concentration (EC 2B receptor or 5-HT 2C receptor, etc.) of the disclosed compound for the 5-HT 2A receptor compared to another receptor (e.g., a serotonin receptor such as the 5-HT 50 ). For example, if a hypothetical compound has an EC 2A of 0.2 μM for 5-HT 50 and an EC 2A of 1.0 μM for 5-HT 50 , it can be said that the compound has 5-fold selectivity for the 5-HT 2B receptor over the 5-HT 2A receptor. In embodiments, the disclosed compounds have about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold selectivity for the 5-HT 2B receptor over the 5-HT 2A receptor. In embodiments, the disclosed compounds have about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold selectivity for the 5-HT 2C receptor over the 5-HT 2A receptor.

[0224] In some embodiments, the disclosed compounds have an increased association rate in serotonin receptors such as the 5-HT2 receptor (e.g., 5-HT 2A , 5-HT 2B , and 5-HT 2A ) compared to a comparator. In some embodiments, the disclosed compounds have an increased association rate in serotonin receptors such as the 5-HT2 receptor (e.g., 5-HT 2A , 5-HT 2B, and 5-HT 2A ) have a reduced association rate at serotonin receptors such as. In an embodiment, the comparator is serotonin. In an embodiment, the comparator is the corresponding unsubstituted phenylalkylamine. In an embodiment, the comparator of XOB is 2C-B. In an embodiment, 5-HT 2A , 5-HT 2B , and 5-HT 2A The association rate of the disclosed compounds in any one or more of is increased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold. In an embodiment, 5-HT 2A , 5-HT 2B , and 5-HT 2A The association rate of the disclosed compounds in any one or more of is decreased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold. For example, in an embodiment, the association rate of XOB at 5-HT 2A is about 24 times slower than the association rate of serotonin (see Example 2).

[0225] c. Regulation of neurotransmission In some embodiments, the disclosed compounds regulate neurotransmission in the subject, such as after administration of a therapeutically effective amount to the subject. In an embodiment, the regulation of neurotransmission by administering the disclosed compound to a subject treats the disease or disorder of the subject.

[0226] In some embodiments, regulating neurotransmission includes regulating serotonergic neurotransmission. In some embodiments, the disclosed compounds can regulate the activity of 5-HT receptors (5-HTRs). 5-HTRs are G protein-coupled receptors (GPCRs) that act via the Gαi, Gαq / 11, or Gαs pathways and affect various signaling mechanisms throughout the body. Regulation of such receptors results in both distinct and overlapping pharmacological effects (Zieba et al., Int J Mol Sci., 2022;23(1):10).

[0227] Each of the three 5-HT2 receptor subtypes is a G-protein coupled single protein molecule of similar size and homology, containing 458 - 471 amino acids. The three subtypes of the 5-HT2 receptor, 5-HT 2A , 5-HT 2B , and 5-HT 2C have been pharmacologically characterized, and functional activities such as agonism and antagonism can be determined according to specific events in the resulting signal transduction cascade. See, for example, Pithadia & Jain, J Clin Med Res. 2009;1(2):72 - 80 and Raote et al., “Serotonin Receptors in Neurobiology,” Chapter 6, Boca Raton (FL): CRC Press / Taylor & Francis; 2007.

[0228] 5-HT 2A activation results in the activation of the GPCR subunit Gαq / 11 and the effector enzyme phospholipase C (PLC), which promotes the release and accumulation of inositol trisphosphate (IP3), diacylglycerol (DAG), and PKC (Singh et al., Int’l J Neuropsychopharmacol, 2009;12(5):651 - 665). In one example, the released inositol phosphate (IP) can be used as an indicator of 5-HT2 receptor signaling activity. See, for example, 5-HT 2A , 5-HT 2B and 5-HT 2C receptors: reference to inositol monophosphate (IP-1) formation in Eshleman et al., Biochem Pharmacol, 2018;158:27 - 34. Further, the accumulation of IP3 causes the release of calcium, which 2+ loads the cell with a Ca 2+It can be monitored by measuring the spectral shift resulting from the binding of the dye. The 5-HT2 receptor function assay method is described, for example, in Klein et al., ACS Pharmacol Transl Sci. 2021;4(2):533-542.

[0229] The accumulation of IP3 itself, for example, the accumulation of total radiolabeled IP such as inositol monophosphate, inositol diphosphate, and inositol triphosphate, can also be used to measure receptor activation and desensitization, including the temporal aspect. In one example, a decrease in the basal level of IP3 provides a measure of antagonism (Raote et al., “Serotonin Receptors in Neurobiology,” Chapter 6, Boca Raton (FL): CRC Press / Taylor & Francis; 2007).

[0230] In some embodiments, the disclosed compounds can modulate the activity of 5-HT receptors, including any of activation, inhibition, partial activation, and partial inhibition of the receptor activity. In embodiments, the disclosed compounds are 5-HT receptor ligands that bind to, activate, block, inhibit, or otherwise affect the activity at 5-HT receptors, for example, via allosteric modulation. In embodiments, the disclosed compounds are 5-HT2 receptor ligands, for example, 5-HT 2A receptor, 5-HT 2B receptor, and 5-HT 2C ligands for one or more of the receptors.

[0231] In some embodiments, the disclosed compounds agonize the 5-HT2 receptor. In embodiments, the disclosed compounds antagonize the 5-HT2 receptor. In embodiments, the disclosed compounds partially agonize the 5-HT2 receptor. In embodiments, the disclosed compounds partially antagonize the 5-HT2 receptor. (See, for example, Example 2; Figure 1) In embodiments, the 5-HT2 receptor is the 5-HT 2A receptor. In embodiments, the 5-HT2 receptor is 5-HT2B is a receptor. In embodiments, the 5-HT2 receptor is 5-HT 2C is a receptor.

[0232] In some embodiments, the disclosed compounds have an in vitro EC 2A for 5-HT 2B , and 5-HT 2A of less than 10 μM, less than 5 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM (agonist mode). In embodiments, the disclosed compounds have an in vitro EC 50 for 5-HT 2A , 5-HT 2B , and 5-HT 2A of about 10 μM, 5 μM, 1 μM, 0.5 μM, or 0.1 μM (agonist mode). In embodiments, the disclosed compounds have an in vitro EC 50 for 5-HT 2A , 5-HT 2B , and 5-HT 2A of less than 10 μM, less than 5 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM (antagonist mode). In embodiments, the disclosed compounds have an in vitro EC 50 for 5-HT 2A , 5-HT 2B , and 5-HT 2A of about 10 μM, 5 μM, 1 μM, 0.5 μM, or 0.1 μM (antagonist mode). For example, XOB antagonizes 5-HT 50 with an EC 50 of 1.3 μM. 2A

[0233] In some embodiments, modulating neurotransmission includes modulating voltage-dependent ion channel activity. In embodiments, the disclosed compounds modulate voltage-dependent calcium ion (Ca 2+ ) channels, voltage-dependent chloride ion (Cl - ) channels, voltage-dependent potassium ion (K +) channels and one or more activities of voltage-gated sodium ion (Na + ) channels (VGSCs).

[0234] In some embodiments, the disclosed compounds have a binding affinity for VGSCs of less than 10 μM, less than 5 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In embodiments, the disclosed compounds have a binding affinity for VGSCs of about 10 μM, 5 μM, 1 μM, 0.5 μM, or 0.1 μM. In embodiments, the disclosed compounds have an increased binding affinity for VGSCs compared to a comparator. In embodiments, the comparator is serotonin. In embodiments, the comparator is the corresponding unsubstituted phenylalkylamine. In embodiments, the comparator of XOB is 2C-B. For example, XOB has a binding affinity for 5-HT 2A of 2.6 μM (see Example 2). In comparison, 2C-B is not known to bind to VGSCs. In embodiments, the binding affinity of the disclosed compounds for VGSCs is increased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 500-fold, 1000-fold or at least 1000-fold compared to the comparator.

[0235] In some embodiments, the disclosed compounds are VGSC inhibitors. In embodiments, the disclosed compounds have an in vitro IC 50 for VGSCs of less than 10 μM, less than 5 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In embodiments, the disclosed compounds have an in vitro IC 50 for VGSCs of about 10 μM, 5 μM, 1 μM, 0.5 μM or 0.1 μM. For example, XOB is a VGSC inhibitor with an IC 50 of 4.29 μM (see Example 2).

[0236] b. Treatment In some embodiments, the disclosed compounds are used to treat medical conditions such as diseases or disorders. In embodiments, the disclosed compounds are used in the manufacture of a medicament for treating a condition such as a disease or disorder. Also provided is a method of administering a disclosed compound to a subject having a condition such as a disease or disorder, thereby treating said condition.

[0237] In some embodiments, the disclosed compounds and pharmaceutical compositions thereof are used to treat serotonin-mediated disorders. In embodiments, the disclosed compounds, when administered to a subject in a pharmacologically effective amount, provide a beneficial therapeutic effect for the treatment of serotonin-mediated disorders. Serotonin-mediated disorders include, for example, mental health disorders, neurodegenerative diseases, pain syndromes, headaches such as migraine, and inflammation.

[0238] In some embodiments, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds are administered to a subject by one or more routes of administration including, for example, oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhalation, ocular, intraocular, topical and transdermal routes. When administered via one or more of such routes, the disclosed compound(s) as well as the disclosed compositions and formulations containing them are useful in methods of treating patients in need of such treatment.

[0239] In an embodiment, the present invention provides a method for treating and / or preventing a mammalian condition, the method comprising administering to a mammal a therapeutically effective amount of a disclosed compound or pharmaceutical composition. In some embodiments, "treating" or "treatment" refers to treating a disease or disorder in a mammal, preferably a human, and causing a desired biological or pharmacological effect, for example: (a) preventing the occurrence of a disorder in a subject who may have a predisposition to the disorder but has not yet been diagnosed with the disorder; (b) inhibiting the disorder, i.e., arresting its onset; (c) alleviating the disorder, i.e., causing its regression; (d) protecting against, or alleviating, symptoms or conditions caused by or associated with the disorder; (e) reducing, decreasing, inhibiting, improving, or preventing the onset, severity, duration, progression, frequency, or likelihood of one or more symptoms or conditions associated with the disorder; and (f) preventing or inhibiting the exacerbation or progression of symptoms or conditions associated with or co-existing with the disorder. Other such measures, benefits, and surrogate or clinical endpoints will be understood by those skilled in the art based on the teachings herein and the knowledge in the art, either alone or in combination.

[0240] As used herein, "effective amount", "pharmacologically effective amount" or "therapeutically effective amount" refers to an amount of an active agent that is non-toxic and sufficient to provide a desired therapeutic effect at a reasonable benefit / risk ratio associated with any medical treatment. The effective amount will vary depending on the subject and the disease state being treated or the desired health benefit, the subject's weight and age, the severity of the disease state or the degree of the desired health benefit, the method of administration, etc., all of which can be readily determined by one of ordinary skill in the art.

[0241] As used herein, "treatment effect" or "treatment efficacy" means a response(s) in a mammal, preferably a human, after treatment that is determined to be desirable and beneficial. Thus, these responses will vary depending on the disorder being treated, or the mental health or functional improvement sought, and on the specific component(s) of the formulation of the invention under consideration, but will be readily understood by one of ordinary skill in the art.

[0242] Measures of treatment effect include any outcome measure, endpoint, effect measure, or measure of effect in a clinical or medical practice or study used to evaluate the outcome of an intervention or treatment, whether reported by the patient (e.g., via questionnaire) or based on other patient data (e.g., patient monitoring), collected through laboratory tests such as blood tests, urine samples, through medical examinations by a physician or other healthcare professional, or by digital tools or means, such as online tools, smartphones, wireless devices, biosensors, or electronic tools such as health apps, and includes measures of both positive and negative effects.

[0243] In some embodiments, the measure of treatment effect includes an assessment. "Assessment" refers to any means or method used with a patient to qualitatively or quantitatively measure, estimate, or evaluate the nature, capabilities, symptoms, impairments, or other characteristics of the patient, before, during, after, or independent of time with respect to a particular treatment protocol, whether performed by a therapist or other clinician (e.g., an interview), by the patient himself or herself (e.g., a self-report questionnaire), by a third party, by a computer including a medical device (e.g., as defined by the FDA or other regulatory agency) or other device (e.g., a medical sensor or biosensor, a wristwatch or fitness tracker, or a "wearable"), and whether rated by a human decision maker or by artificial intelligence, machine learning, or a computer algorithm. The assessment may be computer-assisted, and other computer-assisted assessments may be performed in addition to the assessments described above. The term "computer-assisted" in "computer-assisted assessment" means an assessment that includes the use of electronic tools such as online tools, smartphones, wireless devices, or health apps (in some such examples, also known as "digital phenotyping"). Computer-assisted assessment includes the use of an electronic psychiatric note system in which relevant clinical information is recorded during treatment by a therapist who interacts with the patient in person, as well as computer systems in which the therapist and patient interact virtually (synchronously or asynchronously), and in which the patient interacts only with a computer (the "computer" broadly means any electronic tool suitable for such purposes, including desktop, laptop, and notebook computers; tablets, smartphones, and other mobile devices; wristwatches, fitness trackers, and personal electronic devices). One or more other aspects of psychosocial, behavioral, or pharmacologically assisted therapy may also be "computer-assisted", and one or more steps of such therapy include, in addition to or instead of some of the tasks that would otherwise be performed by a therapist, the use of a computer.

[0244] i. Mental disorder, behavioral disorder, or neurodevelopmental disorder In some embodiments, the disclosed compounds are used to treat mental disorders, behavioral disorders, or neurodevelopmental disorders. In some embodiments, the disclosed compounds are administered, for example, in a therapeutically effective amount, to a subject having a mental disorder, behavioral disorder, or neurodevelopmental disorder, thereby treating the mental disorder, behavioral disorder, or neurodevelopmental disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect for the treatment of mental disorders, behavioral disorders, or neurodevelopmental disorders.

[0245] The ICD-11, which is incorporated herein by reference in its entirety, defines "mental disorder, behavioral disorder, or neurodevelopmental disorder" as a syndrome characterized by clinically significant disorders in an individual's cognition, emotional regulation, or behavior that reflect dysfunction in psychological, biological, or developmental processes underlying mental and behavioral functioning. Such disorders include, but are not limited to, neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically related to stress, dissociative disorders, eating (or feeding) disorders, elimination disorders, disorders of physical pain or physical experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive or antisocial disorders, personality disorders (and related traits), paraphilia disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders related to pregnancy, childbirth, or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.

[0246] Mental, behavioral, or neurodevelopmental disorders not otherwise defined are understood to refer to disorders defined in the ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or "mental health disorder") generally refers to a disease state involving negative changes in mood, affect, thinking, and / or behavior. Generally, mental health disorders are characterized by clinically significant disorders in an individual's cognition, affect, behavior, or combinations thereof that result in impairment, distress, or increased risk of morbidity. The terms "mental disorder" and "mental health disorder," as well as terms defining specific diseases and disorders, generally refer to patients having a diagnosis based on the criteria of the ICD-11 or a diagnosis based thereon, but the disclosed methods are equally applicable to patients having an equivalent underlying disorder whether the disorder is diagnosed based on the criteria of the ICD-11, ICD-10, DSM-5, or DSM-IV (each of which is incorporated herein by reference in its entirety), whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet received a formal clinical diagnosis.

[0247] In some embodiments, the disclosed compounds are used to treat mental health disorders. In some embodiments, the disclosed compounds are administered, for example, in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating the mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide a beneficial therapeutic effect for the treatment of mental health disorders. In some embodiments, the compounds and compositions of the invention are used to alleviate the symptoms of mental health disorders. The symptoms of the mental health disorder to be treated can be determined by one of ordinary skill in the art by reference to the general understanding in the art regarding the disorder.

[0248] In some embodiments, measures of treatment efficacy include reports by the subject or observer. In some embodiments, measures of treatment efficacy include responses to questionnaires. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Pittsburgh Sleep Questionnaire (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Traumatic History Questionnaire (THQ), Beck Depression Index (BDI), and related measures reported by the subject or observer.

[0249] In some embodiments, the disclosed compounds are used to treat schizophrenia (or another primary psychotic disorder as defined in DSM-IV, DSM-5, ICD-10, or ICD-11). Such disorders can be characterized by significant impairments in reality, as well as positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking and speech, severely disorganized behavior, and negative symptoms such as the experience of blunted or flat affect and volition and psychomotor disturbances, manifested by changes in behavior. Serotonin receptors, particularly 5-HT 2A receptors have been targets of antipsychotic therapeutics for decades (Schmidt et al., Life Sci. 1995; 56(25):2209-2222), and recent studies have investigated 5-HT for the treatment of negative symptoms in patients with schizophrenia. 2ASupports the use of antagonists (Romeo et al., Psychiatry Res. 2023;321:115104). In some embodiments, the disclosed compounds are used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or substance-induced psychotic disorder. In some embodiments, measures of treatment efficacy in the treatment of schizophrenia or related psychotic disorders include the Clinical Global Impression Scale (CGI), the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Negative Symptom Assessment Scale (SANS), the Positive Symptom Assessment Scale (SAPS), the 16-Item Negative Symptom Assessment Scale (NSA-16), the Schedule for Deficit Syndrome (SDS), the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptom Scale (BNSS).

[0250] In some embodiments, the disclosed compounds are used to treat mood disorders. As defined in the ICD-11, mood disorders are classified according to specific types (one or more) of mood episodes and their patterns over time, and the main types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. 5-HT 2A Receptor antagonism is a common mechanism of many FDA-approved antipsychotics used in the treatment of mood disorders (Casey et al., Biochem. Pharmacol. 2022;200:115028). In some embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar I disorder, bipolar II disorder, cyclothymic disorder), a depressive disorder (e.g., single-episode depressive disorder, recurrent depressive disorder, mood-disorder with modulation, mixed anxiety-depressive disorder), or a substance-induced mood disorder. In some embodiments, measures of treatment efficacy in the treatment of mood disorders (e.g., bipolar disorder) include the General Behavior Inventory (GBI), the Mood Disorder Questionnaire (MDQ), the Young Mania Rating Scale, the Beck-Rafaelson Mania Rating Scale, the Altman Self-Rating Mania Scale, and the Self-Report Mania Questionnaire.

[0251] ii. Neurodegenerative disorders In some embodiments, the disclosed compounds and compositions thereof are used to treat neurodegenerative conditions. In embodiments, a therapeutically effective amount of the disclosed compound or a pharmaceutical composition thereof is administered to a subject in need thereof to treat a neurodegenerative condition. In some embodiments, administration of a therapeutically effective amount of the disclosed compound slows or prevents the progression of neurodegeneration. In embodiments, administration of a therapeutically effective amount of the disclosed compound decreases the incidence or severity of at least one symptom of a neurodegenerative condition.

[0252] Neurodegeneration can be assessed, for example, by measuring markers of neuronal loss such as cerebrospinal fluid markers, such as visinin-like protein 1 (VILIP-1), tau, and p-tau181 (Tarawneh et al., Neurol. 2015;72(6):656-665). Cognitive decline can also be used as a measure of neurodegeneration. Methods for assessing cognitive decline, such as comprehensive neuropsychological tests, are known to those of skill in the art. Exemplary cognitive assessments include the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). See, for example, Toh et al., Transl Neurodegener. 2014;3:15. Cognitive decline and disease progression can also be evaluated using condition-specific scales, such as the Unified Huntington's Disease Rating Scale (UHDRS).

[0253] Examples of neurodegenerative conditions such as diseases or disorders include, for example, dementia, Alzheimer's disease, Huntington's disease, multiple sclerosis, and Parkinson's disease. The characteristic of neurodegenerative conditions is neuronal cell death, which is involved in promoting inflammation among other aspects. See, for example, Chan et al., Annu Rev Immunol. 2015;33:79-106 and Chi et al., Int J Mol Sci. 2018;19(10):3082. Neurodegenerative diseases can be classified according to major clinical features such as dementia, parkinsonism or motor neuron disease, the anatomical distribution of neurodegeneration such as frontotemporal degeneration, extrapyramidal disorders or spinocerebellar degeneration, or major molecular abnormalities (Dugger & Dickson, Cold Spring Harb Perspect Biol. 2017;9(7):a028035).

[0254] iii. Pain and inflammation In some embodiments, the disclosed compounds and compositions thereof are used to treat pain disorders and / or inflammation. In an embodiment, a therapeutically effective amount of the disclosed compound or a pharmaceutical composition thereof is administered to a subject in need thereof to treat a pain disorder and / or inflammation. In an embodiment, administration of a therapeutically effective amount of the disclosed compound reduces the incidence or severity of at least one symptom of a pain disorder and / or an inflammatory disorder.

[0255] In some embodiments, the pain disorder treated by the disclosed compounds is a chronic pain disorder. Examples of chronic pain disorders include, for example, central pain, complex regional pain syndrome, phantom limb pain such as phantom limb pain, neuropathic pain, fibromyalgia, arthritis, spinal stenosis, temporomandibular joint syndrome, bowel disease, pain associated with surgery, and pain associated with a disease or disorder such as cancer-associated pain.

[0256] In some embodiments, the disclosed compounds and their compositions are used to treat headache. In an embodiment, a therapeutically effective amount of the disclosed compound or its composition is administered to a subject in need thereof to treat headache. Headache includes, for example, tension headache, migraine and cluster headache.

[0257] In some embodiments, the disclosed compounds and their compositions are used to reduce inflammation, such as systemic inflammation. In an embodiment, the disclosed compounds and their compositions are used to treat inflammatory diseases. In an embodiment, a therapeutically effective amount of the disclosed compound or its pharmaceutical composition is administered to a subject in need thereof to treat an inflammatory disease. Examples of inflammatory diseases include, but are not limited to, Alzheimer's disease, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease, and ulcerative colitis.

[0258] The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." 5-HT 2A agonists and 5-HT 2A antagonists and other serotonin modulators remain unclear as to how they improve pain, but the synaptic plasticity associated with such compounds may modify the pathological changes in neural connections seen in chronic pain states and potentially lead to a reduction in pain intensity and duration (Castellanos et al., Reg Anesth Pain Med. 2020;45(7):486-494). Furthermore, 5-HT 2AR activation has been shown to promote anti-inflammatory effects, such as a reduction in TNF-α-induced inflammation. See, for example, Pelletier & Siegel, Mol Interv., 2009, 9(6):299-301, Flanagan et al., Sci Rep. 2019;9(1):13444, Nichols et al., Clin Pharmacol Ther. 2017;101(2):209-219; Int Rev Psychiatry. 2018;30(4):363-375, Okamoto et al., Neuroscience. 2005;130(2):465-74.

[0259] Pain, such as chronic pain, and its improvement, such as symptom reduction, can be measured according to known methods, for example, by subject reports, pain diaries, pain scales, applicable questionnaires (evaluation of chronic pain and its impact on physical, emotional, and social function), ecological time-course evaluations, and computerized versions thereof. See, for example, Salaffi et al., Best Practice & Research Clinical Rheumatology, 2015;29(1):164-186 and Hawker et al., Arthritis Care Res (Hoboken). 2011;63 Suppl 11:S240-52. Exemplary questionnaires include the Visual Analogue Scale for Pain (VAS Pain), Numerical Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form 36 Bodily Pain Scale (SF-36 BPS), and Intermittent and Constant Osteoarthritis Pain Scale (ICOAP), migraine diagnostic questionnaire, migraine screening questionnaire (MS-Q), fibromyalgia survey questionnaire (FSQ).

[0260] Reduction of inflammation, such as chronic systemic inflammation, can be measured according to various methods available to those skilled in the art. Inflammatory biomarkers can be detected from biological specimens, such as the blood of a subject, such as plasma or serum, or saliva. In one example, inflammation can be detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test. CRP can also be detected in saliva samples. Salivary CRP is not locally synthesized in the oral cavity and can reflect a more systemic level of inflammation compared to other inflammatory biomarkers such as cytokines (Szabo & Slavish, Psychoneuroendocrinology. 202;124:105069). Additionally, clinical pathology data, such as erythrocyte parameters, platelet count, total white blood cell count, and hematological data regarding white blood cell differentiation and morphology, coagulation data regarding clotting time and fibrinogen, and clinical chemistry data regarding total protein, albumin and globulin, liver enzymes, kidney parameters, electrolytes, and bilirubin can provide initial indicators of the presence and potential location of inflammation in the absence of specific data regarding the immune tissue. See, for example, Germolec et al., Methods Mol Biol. 2018;1803:57-79 and Luo et al., Clin Lab. 2019 1;65(3).

[0261] iv. Ion channel-mediated symptoms In some embodiments, the disclosed compounds and their compositions are used to treat ion channel-mediated symptoms. "Ion channel-mediated symptoms" refers to a disease or disorder associated with the dysfunction of an ion channel, such as a voltage-dependent ion channel or a ligand-dependent ion channel. In an embodiment, a therapeutically effective amount of the disclosed compound or its pharmaceutical composition is administered to a subject in need thereof to treat ion channel-mediated symptoms. In an embodiment, the ion channel-mediated symptoms are one or more of a calcium ion (Ca 2+ ) channel, a chloride ion (Cl - ) channel, a potassium ion (K + ) channel, and a sodium ion (Na + ) channel.

[0262] In some embodiments, the disclosed compounds modulate the activity of one or more of calcium ion (Ca 2+ ) channels, chloride ion (Cl - ) channels, potassium ion (K + ) channels, and sodium ion (Na + ) channels. In embodiments, the ion channels are voltage-dependent. In embodiments, the ion channels are ligand-dependent. In embodiments, the disclosed compounds modulate the activity of one or more of voltage-dependent calcium ion (Ca 2+ ) channels, voltage-dependent chloride ion (Cl - ) channels, voltage-dependent potassium ion (K + ) channels, and voltage-dependent sodium ion (Na + ) channels. In embodiments, modulating the activity of an ion channel includes blocking the ion channel, e.g., inhibiting or reducing the activity of the ion channel. In embodiments, modulating the activity of an ion channel includes activating the ion channel.

[0263] In some embodiments, the disclosed compounds or compositions thereof are used to treat seizure disorders such as epilepsy. In embodiments, a therapeutically effective amount of the disclosed compound or a pharmaceutical composition thereof is administered to a subject in need thereof to treat a seizure disorder. In embodiments, administration of a therapeutically effective amount of the disclosed compound reduces the incidence of seizures and / or the severity of the seizure disorder. In embodiments, the seizure disorder is an epileptic seizure disorder. In embodiments, the seizure is a focal seizure. In embodiments, the seizure is a generalized seizure. In embodiments, administration of the disclosed compound to a subject results in, for example, a reduction in the severity of epilepsy comorbidities, such as anxiety and depression, and / or an improvement in quality of life, as evaluated using, for example, the Quality-of-Life questionnaire in Epilepsy (QOLIE-31).

[0264] A seizure is a burst of uncontrolled electrical activity between neurons that causes a temporary abnormality in muscle tone or movement, behavior, sensation, or state of consciousness (Types of Seizures, Johns Hopkins Med., accessed June 24, 2022). Ion channels are important components of neuronal function due to their role in maintaining cellular ion and electrical homeostasis. Specific subunits are expressed only in the brain, and ion channel dysfunction can cause epilepsy, which is characterized by recurrent seizures (Armijo et al., Curr Pharm Des. 2005;11(15):1975-2003; Graves, QJM: Int’l J Med., 2006;99(4):201-217). The various antiepileptic treatment options reduce membrane excitability by interacting with neurotransmitter receptors or ion channels. For example, phenytoin and carbamazepine inhibit sodium channel activation, thereby reducing the high-frequency repetitive firing of associated action potentials (Macdonald & Kelly, Epilepsia. 1995;36 Suppl 2:S2-12). Non-limiting examples of comorbidities of epilepsy that may benefit from the disclosed compounds include depression, anxiety, and migraine (Keezer et al., Lancet Neurol. 2016;15(1):106-15).

[0265] The determination of whether the disclosed compounds modulate the activity of ion channels can be achieved by monitoring the electrophysiological activity of cells. For example, patch clamp techniques enable the measurement of the current passing through ion channels in the cell membrane. See, for example, Lenkey et al., PLoS One. 2010;5(12):e15568, Liu et al., Assay Drug Dev Technol. 201;9(6):628-34, and Dolzer, Methods Mol Biol. 2021;2188:21-49. Patch clamp experiments can be performed on cultured cells, acutely dissociated cells, or acute vibratome slices. Additionally, fluorescence resonance energy transfer (FRET) techniques using membrane potential-sensitive dyes can provide measurements of voltage-dependent sodium channel activity in stably transfected cell lines (Felix et al., Assay Drug Dev Technol. 2004 Jun;2(3):260-8).

[0266] v. mental function In some embodiments, the present invention provides a method for improving functions such as mental health and / or cognitive function. Improving mental health and function may include one or more of a decrease in neuroticism or psychological defense, an increase in creativity or openness to experience, an increase in decision-making ability, an increase in sense of health or satisfaction, or an increase in the ability to fall asleep or stay asleep. Further, improving mental health and function may include an improvement in processing speed, learning and memory, autobiographical memory, shifting, and IQ or a return to baseline. Such measures will be readily understood and recognized by those skilled in the art. See, for example, the aspects of cognitive function reviewed by Ahern & Semskova, Neuropsychology. 2017;31(1):52-72. Exemplary measures of improving mental health and / or function include the Global Assessment of Functioning (GAF) scale, the Sleep Quality Scale (SQS) and other measures of sleep quality (see, for example, Fabbri et al., Int J Environ Res Public Health. 2021;18(3):1082), as well as the Social Functioning Scale (SFS) (see, for example, Chan et al., Psychiatry Res. 2019;276:45-55). In some embodiments, the present invention provides a method for improving functions such as mental health and / or cognitive function in healthy people such as "healthy normals", and thus the present invention includes, in some embodiments, "betterment of the well".

[0267] vi. Co-administration with psychotherapy In some embodiments, the disclosed compound or composition thereof is administered together with a psychosocial or behavioral therapy, such as cognitive behavioral therapy (e.g., as described in Arch. Gen. Psychiatry, 1999;56:493 - 502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168 - 174), contingency management - based therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168 - 174; J. Consul. Clin. Psychol., 2005;73(2):354 - 59; or Case Reports in Psychiatry, Vol. 2012, Article ID 731638), motivation - interviewing - based therapy (e.g., as described in J. Consul. Clin. Psychol., 2001;69(5):858 - 62), or meditation - based therapy, such as transcendental meditation - based therapy (e.g., as described in J. Consul. Clin. Psychol. 2000;68(3):515 - 52) (or adapted from any of them).

[0268] In some embodiments, the disclosed compounds or compositions thereof are administered in combination with psychotherapy. "Psychotherapy" can refer to "psychedelic-assisted psychotherapy." Psychedelic-assisted psychotherapy broadly includes various related approaches that include at least one session in which a patient ingests a psychedelic drug and is monitored, supported, or otherwise engaged by one or more trained mental health professionals while under the influence of the psychedelic drug (see, e.g., Schenberg, Front. Pharmacology, 2018;9(733)). Protocols have been developed for the standardization of procedures that emphasize high-level care, such as the treatment approach used by MAPS to treat patients with PTSD using MDMA (see, e.g., A Manual for MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder (2015), published by the Multidisciplinary Association for Psychedelic Studies (MAPS) and available at http: / / www.maps.org / research-archive / mdma / MDMA-Assisted-Psychotherapy-Treatment-Manual-Version7-19Aug15-FINAL.pdf) (see, e.g., Johnson et al., J. Psychopharmacol., 2008;22,603-620).

[0269] In some embodiments, the psychotherapy conducted using the compounds or compositions of the present invention is carried out in widely spaced sessions, typically with two administrations of the compounds of the present invention per session (a first dose and a “booster” dose, although in some embodiments, a single dose only). These sessions can be at a frequency of once a week, but more often are approximately once a month or less. In most cases, approximately one to three fewer sessions are required for the patient to experience significant clinical progress, as indicated, for example, by reduction in the symptoms of the mental health disorder being treated. In some embodiments, the psychotherapy includes multiple sessions, with administration of the compounds of the present invention during some of them (the “psychedelic-assisted psychotherapy” and also “medication-assisted psychotherapy” described above); in other cases, the patient participates in psychosocial or behavioral therapy without concomitant administration of the drug or without administration of the compounds of the present invention.

[0270] In some embodiments, the compounds or compositions of the present invention are administered once a week, twice a week, or as needed, directly in person or virtually (e.g., via telemedicine, or using a web program or mobile application), with a standardized psychological treatment or support that refers to any accepted modality of standard psychotherapy or counseling sessions by a human therapist or a virtual or AI “therapist”. As used herein, “therapist” refers to a person who treats a patient using the compositions and methods of the present invention, regardless of whether that person is a psychiatrist, clinical psychologist, clinical therapist, registered therapist, psychotherapist, or other trained clinician, counselor, facilitator, or guide, although it will be understood that specific requirements are met for particular aspects of medication-assisted therapy (e.g., prescribing, dispensing, or administering the drug, providing psychotherapeutic support). In some embodiments, “person” can also include AI.

[0271] In some embodiments, a patient participates in a treatment protocol or method of the invention or is administered a composition of the invention as part of such method if the patient meets certain specified inclusion criteria, does not meet certain specified exclusion criteria, and does not meet specified withdrawal criteria during the course of treatment and otherwise meets the requirements of the claimed embodiments of the invention.

[0272] Preferably, when the pharmaceutical composition of the invention is administered, such administration is carried out without or with a reduced risk of side effects that require medical supervision and thus enables treatment to be carried out at home or otherwise outside a clinic without such supervision and / or additionally without the need for adjunctive psychotherapy (although this may also be provided in certain embodiments herein).

[0273] In some embodiments, the compounds and compositions of the invention can be administered in combination with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither required nor desirable, or a particular type of psychotherapy is neither required nor desirable, but any of the disclosed methods can be used in combination with one or more psychotherapy sessions. The flexibility to participate in a particular therapy and to choose between (or decide to discontinue any such therapy) while still receiving a clinically significant treatment effect is one of the advantages of the invention.

[0274] In some embodiments, a patient will participate in one or more therapeutically beneficial activities, such participation occurring subsequent to or in conjunction with the administration of the provided compound or composition and including breathing exercises, meditation and concentration exercises, focusing on an object or mantra, listening to music, physical movement, yoga, stretching or massage, journaling, grounding techniques, positive self-talk, or interaction with a pet or animal, it being understood that such participation can occur with or without the participation or guidance of a therapist.

[0275] H. Example The following examples are included for illustrative purposes only and are not intended to limit the scope of the present invention.

[0276] General methods and procedures Drugs and reagents: All drug recording solutions used in electrophysiology experiments were prepared on the day of recording. XOB was dissolved in 100% ethanol (EtOH). Tetrodotoxin citrate (TTX) was obtained from Alomone Labs (Jerusalem, Israel). Reagents and solvents were obtained from Sigma-Aldrich (St. Louis, MO) or other described commercial sources.

[0277] Statistical analysis: All data analysis of the recorded INa was performed using the software packages Clampfit v10.4 (Molecular Devices), Microsoft Excel, and Graph Pad Prism v9.0 (San Diego, CA). The active and passive neuronal properties of brain slice recordings were analyzed using custom MATLAB (MathWorks) software. Unless otherwise specified, results are presented as mean ± S.E.

[0278] Example 1 Synthesis of XOB The test compound N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) was synthesized according to Scheme 1. [Chemical formula] Scheme 1. Synthesis of N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB). XOB was obtained in 50% yield from 2C-B by condensation with (4-((6-bromohexyl)oxy)butyl)benzene in acetonitrile. Purification was by silica gel column chromatography, eluting with a mobile phase of CH2Cl2:MeOH 95:5 containing 10 mM triethylamine.

[0279] 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) was synthesized according to the method of Shulgin and Carter (Shulgin and Shulgin 1975 #715). The 2C-B free base (5.74 g, 22.07 mmol) was dissolved in 50 mL of acetonitrile with stirring to give a colorless transparent solution. When triethylamine (4.22 mL, 30.0 mmol) and sodium iodide (126 mg, 0.758 mmol) were added, the mixture became slightly milky. Stirring was continued for 10 minutes, then (4-((6-bromohexyl)oxy)butyl)benzene (5.21 mL, 18.04 mmol) was added with continued stirring. The turbid reaction mixture became slightly exothermic and rose from 18.7 °C to 21.2 °C over 90 minutes. The reaction was stirred at ambient temperature and the progress was monitored by TLC (silica gel, MeOH:CH2Cl2 1:9). After 144 hours, the reaction had turned orange and was considered complete. The reaction mixture was filtered and the volatiles were removed by rotary evaporation to give approximately 11.8 g of an orange waxy solid. This crude product was dissolved in 60 mL of a mobile phase consisting of CH2Cl2:MeOH 95:5 containing 10 mM triethylamine and chromatographed on a 4.8 cm × 30 cm silica gel (600 g, 200 - 400 mesh) column. The positive 20 mL fractions were collected, combined, and then the volatiles were removed by rotary evaporation to give 4.43 g (50% yield from 2C-B) of N-(4-bromo-2,5-dimethoxy-phenethyl)-6-(4-phenyl-butoxy)hexan-1-amine (XOB) as a pale yellowish-brown waxy solid.

[0280] 1 The predicted structure was confirmed by analysis using \(^1H\) NMR (Figure 2), GC / MS (Figure 3), and LC / MS / MS (Figures 4A, 4B, and 5).

[0281] NMR: The proton NMR spectra were acquired in \(CDCl_3\) containing 0.1% tetramethylsilane (TMS) using a 500 MHz Bruker Avance NEO spectrometer equipped with an iProbe. 2D COSY spectra were acquired to clearly assign the resonances. 1 \(^1H\) NMR (500 MHz, \(CDCl_3\)) \(\delta\) 1.38 (4H, m, \(J = 6.5\) Hz), \(\delta\) 1.55 (2H, p, \(J = 7\) Hz), \(\delta\) 1.61 (2H, m, \(J = 2.5\) Hz), \(\delta\) 1.68 (2H, m, \(J = 2.5\) Hz), \(\delta\) 1.93 (2H, p, \(J = 7\) Hz), \(\delta\) 2.64 (2H, t, \(J = 7\) Hz), \(\delta\) 2.97 (2H, p, \(J = 7\) Hz), \(\delta\) 3.22 (4H, m, \(J = 5.5\) Hz), \(\delta\) 3.34 (2H, t, \(J = 6.5\) Hz), \(\delta\) 3.40 (2H, t, \(J = 6.5\) Hz), \(\delta\) 3.78 (3H, s), \(\delta\) 3.85 (3H, s), \(\delta\) 6.91 (1H, s), \(\delta\) 7.04 (1H, s), \(\delta\) 7.18 (3H, d, \(J = 7\) Hz), \(\delta\) 7.28 (2H, t, \(J = 7\) Hz)

[0282] GC - MS: Samples were dissolved in ethyl acetate for GC - MS analysis using an Agilent 6890 gas chromatograph equipped with a 7673 autosampler / injector and an Agilent 5973 mass - selective detector (MSD) system. GC - MS parameters: The injector was operated in splitless mode, injector temperature, \(250^{\circ}C\); injection volume, 1 \(\mu L\); column, Agilent 19091A - 105 HPULTRA1, 50 m × 0.20 mm × 0.33 \(\mu m\) film thickness; oven temperature, \(50^{\circ}C\) for 0.5 min, raised to \(95^{\circ}C\) (10 \(^{\circ}C\) / min), held for 2 min, raised to \(260^{\circ}C\) (20 \(^{\circ}C\) / min), held for 4.75 min; carrier gas, hydrogen; pressure, 10 psi; flow rate, 29.6 mL / min; MSD transfer line heater temperature, \(280^{\circ}C\); MS scan range, m / z 40 - 500; total run time, 20 min.

[0283] LC MS-MS: Liquid chromatography high-resolution mass spectrometry (LC-HRMS) was performed using a Waters Acquity I-Class UPLC system equipped with a Waters HSS T3 column (particle size 2.5 μm, dimensions 2.1 mm × 30 mm). This system was operated in gradient mode at a flow rate of 0.6 mL / min using a mobile phase of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. Samples for analysis were prepared by diluting with a mixture of acetonitrile and water (1:1 v / v) to obtain a final concentration of 1 mg / mL. Subsequently, 0.1 μL aliquots from this prepared solution were injected for analysis. Evaluation of chemical purity was achieved by integrating chromatographic peaks at a wavelength of 269 nm using a photodiode array (PDA) detector. Acquisition of high-resolution mass spectra was achieved inline with the PDA detector using a Waters Xevo G2-XS quadrupole time-of-flight (QTof) mass spectrometer operating in ESI positive mode. For both low and high collision energy mass spectra, data were recorded using a Waters MSe experiment and processed using Unifi software (version 1.8).

[0284] Example 2 Pharmacology of XOB Objective: Based on the amino acid sequence alignment between the human β2 receptor and the human 5-HT 2A receptor (see, for example, FIGS. 6-10), similar to the β2 receptor, 5-HT 2A receptor was hypothesized to contain an exosite that could engage the extended N-linked side chain of a modified 5-HT 2A agonist. To test this, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexane-1-amine (XOB) was synthesized as a putative probe for the 5-HT 2A exosite. The binding and functional activity of XOB were examined on 5-HT 1A 、5-HT 2A 、5-HT 2B and 5-HT 2CIt was tested on receptors. Furthermore, in initial studies, it was fortuitously observed that XOB produces a profound and long-lasting local anesthetic effect upon contact with mucous membranes. Therefore, to test the hypothesis that XOB also affects electrical signal transmission, the inventors studied the human embryonic kidney (HEK) cells for Na v human voltage-gated sodium channel (VGSC) Na co-expressed with the β1 subunit v 1.1 a subunit and evaluated its acute effect on the sodium current (I Na ). Additionally, patch-clamp electrophysiology was used to test the acute effect of XOB on neuronal excitability in mouse cortical brain slices.

[0285] Methods: Measurement of target engagement in transiently expressed HiBiT-5-HT receptors: The inventors attempted to compare the binding properties of XOB and the endogenous ligand serotonin in several 5-HT receptors using the NanoBRET target engagement assay. This assay quantifies the dynamic interactions between ligands and their cognate HiBiT-tagged GPCRs on the surface of live cells through competitive binding with a fluorescent tracer (Boursier et al., J Biol Chem., 2020;295(15):5124-5135). For this evaluation, the inventors used DNA constructs encoding either the 5-HT 1A 、5-HT 2A 、or 5-HT 2C receptor that are genetically fused to an N-terminal HiBiT tag capable of generating bright luminescence through high-affinity complementation with the non-permeable 18 kDa subunit LgBiT derived from NanoLuc (Killoran et al., Molecules., 2021;26(10):2857).

[0286] First, for each receptor, the binding constant for one of two fluorescent tracers containing the NanoBRET-590 fluorophore conjugated to either clozapine or NAN-190 was determined (Killoran et al., Molecules, 2021;26(10):2857). For this purpose, HEK293 cells transiently expressing the HiBiT-tagged receptor were treated with increasing concentrations of the fluorescent tracer in the absence or presence of excess unmodified ligand (Figs. 11A - 11I). The binding constants (K D ) derived from these saturation binding analyses were 64 nM and 360 nM affinity for the clozapine tracer at the 5-HT 2A and 5-HT 2C receptors, respectively, and 28 nM affinity for the NAN-190 tracer at the 5-HT 1A receptor.

[0287] Having obtained the binding constants of the fluorescent tracers, the inventors further evaluated the binding affinities of unmodified XOB and serotonin at these receptors. HEK293 cells transiently expressing the HiBiT-tagged receptor were tested for competitive displacement of a fixed EC 80 concentration of the fluorescent tracer by increasing concentrations (1 pM - 30 μM) of unmodified XOB or serotonin (Figs. 12A - 12D). Binding constants calculated according to the Cheng-Prusoff equation (Cheng and Prusoff, Biochem Pharmacol., 1973;22(23):3099 - 3108).

[0288] The inventors chose to further compare the binding kinetics of XOB and serotonin at the 5-HT 2A receptor, which may be relevant by prediction of efficacy. First, the rate constants of the clozapine tracer were determined. For this purpose, HiBiT-5-HT 2AHEK293 cells transiently expressing the receptor were treated with various concentrations of clozapine tracer in the presence and absence of excess unmodified clozapine, and binding was observed over 30 minutes (Figure 13). The binding affinity derived from this kinetic analysis was consistent with that obtained from saturation binding experiments, revealing a moderate association rate and a fast dissociation rate. We fixed the EC 80 In the presence of a fixed concentration of clozapine tracer, HiBiT-5-HT 2A Binding of serotonin and XOB to the receptor was further observed over 30 minutes. The binding affinity derived from kinetics was generally equivalent to that obtained from equilibrium analysis, but at the same time, it became clear that the weak potency of XOB for the 5-HT 2A receptor is likely to be emphasized by its slow association rate, which is two orders of magnitude slower than the association rate of serotonin.

[0289] Cell line: Human embryonic kidney (HEK) 293 cells stably expressing the human VGSC α subunit Na v 1.1 (GenBank accession number NP_008851.3) were gifted by Dr. Massimo Mantegazza. The human VGSC β1 subunit (GenBank accession number NP_001028.1) cDNA was transfected into this strain to generate a second stable strain. The cells were cultured in Dulbecco's modified Eagle's medium containing (4.5 g / L D-glucose, L-glutamine, 110 mg / L sodium pyruvate, 200 μg / mL G418, 100 U / mL penicillin / streptomycin). All cells were maintained in an incubator at 37 °C containing 5% CO2.

[0290] Animals: Wild-type C57BL / 6J mice were obtained from Jackson Labs. Male and female pups at postnatal (P) days 17 - 23 were used for electrophysiological experiments. The animals were housed in the Unit for Laboratory Animal Medicine at the University of Michigan. All procedures were carried out in accordance with NIH and approved by the University of Michigan IACUC.

[0291] Manual sodium current recording: Sodium current (I Na) was measured at room temperature using a manual whole-cell patch-clamp technique with the previously described electrophysiological method (Chen et al., J Biol Chem., 2012;287(46):39061-39069). Cells were plated on a transparent glass poly-D-lysine-coated coverslip (Neuvitro) with a diameter of 12 mm and used for electrophysiological recording within 48 hours after plating. Cells were identified using an A1R upright confocal microscope (Nikon). A micropipette was obtained from a glass capillary (Harvard Apparatus) with an outer diameter of 1.5 mm using a P-97 horizontal puller (Sutter Instrument Co.). The micropipette was then polished using an MF-830 microforge (Narishige) to obtain a resistance of 2.0 - 5.0 MΩ. The intracellular solution contained the following (in mM units): 1 NaCl, 125 N-methyl-D-glucamine, 2 MgCl2, 10 EGTA, 40 HEPES, 5 phosphocreatine-tris, 2 Mg-ATP, 0.2 Na2-GTP, 0.1 leupeptin, 270 - 275 mOsm, pH 7.2 with H2SO4. The extracellular solution contained the following (in mM units): 120 NaCl, 1 BaCl2, 2 MgCl2, 0.2 CdCl2, 1 CaCl2, 20 sucrose, 10 glucose, 10 HEPES, 10 tetraethylammonium chloride, 300 - 305 mOsm, pH 7.35 with NaOH. Signals were amplified using a Multiclamp 700B amplifier (Molecular Devices). Data were acquired using a Digidata 1440A interface (Molecular Devices) and analyzed offline using pClamp10. Pipette and whole-cell capacitance were fully compensated, series resistance was predicted and compensated by 50%. Signals were low-pass filtered at 10 kHz and data were sampled at 20 kHz. Residual linear capacitance and leakage current were excluded using online P / 4 subtraction. Gravity-driven perfusion of XOB was used at a flow rate of 2 - 3 mL / min in all manual patch-clamp experiments. All manual whole-cell I recorded under XOB conditions Na was performed after 3.9 minutes of perfusion unless otherwise specified.

[0292] Automated sodium current recording (SyncroPatch): Automated whole-cell sodium current recordings were performed on a SyncroPatch 384 equipped at the University of Michigan Center for Chemical Genomics according to Nanion's standard procedures. A single-hole perforated patch pipette was used. Immediately before recording, HEK 293 cells were dissociated with TryplE, quantified with an automated cell counter (Nano EnTek), and resuspended in the extracellular solution at a concentration of 800,000 cells / mL. The extracellular solution contained the following (in mM): 140 NaCl, 4 KCl, 2 CaCl2, 1 MgCl2, 5 glucose, 10 HEPES, 298 mOsm, pH 7.4 with NaOH. The intracellular solution contained the following (in mM): 110 KF, 10 NaCl, 10 KCl, 10 EGTA, 10 HEPES, 285 mOsm, pH 7.2 with KOH. Currents were digitized at 20 kHz and low-pass filtered at 5 kHz. Series resistance was automatically compensated. Leak subtraction of the current was performed with one or two rectangular pulses stepping from a holding potential of -80 mV to -60 mV for 10 ms using the leak correction method implemented in PatchControl384. The I-V protocol used to examine activation and inactivation was combined, sampled at 10 kHz, and low-pass filtered at 5 kHz. To determine the INa amplitude and the voltage-dependence of activation, I Na was evoked from a holding potential of -80 mV to -120 mV for 500 ms, followed by a prestep to -10 mV for 50 ms. The membrane was hyperpolarized to -120 mV for 500 ms prior to a 500 ms test pulse in the range of -120 mV to +30 mV (in 5 mV increments). Immediately after the test pulse, the voltage-dependence of inactivation was determined by stepping from the same voltage as described for the voltage-dependence of activation to -10 mV for 50 ms. SyncroPatch quality control criteria for the I-V protocol were set to capacitance <35 pF, peak I more negative than -200 pA Na , series resistance of 1 to 35 MΩ, and seal resistance >200 MΩ. Peak I NaNormalized to the cell capacitance to obtain the current density, which was used to plot the I-V curve, and the conductance was calculated using the following equation:

Equation

[0293] where g is the conductance, I is the current, V is the test potential, and V rev is the measured reversal potential. The peak current was normalized to the maximum peak I Na amplitude. The V 1 / 2 of activation represents the voltage of the membrane at which the half-peak I Na amplitude occurred. The normalized voltage dependencies of the activation and inactivation curves were fitted to the following Boltzmann equation:

Equation

[0294] where V 1 / 2 is the membrane potential at the midpoint of the curve and k is the slope factor. The peak I Na protocol was sampled at 20 kHz and low-pass filtered at 5 kHz. The membrane was stepped from a holding potential of -80 mV to -120 mV for 500 ms and then to -10 mV for 500 ms to induce the peak I Na , after which it was returned to -80 mV. The peak I Na protocol was run as a repetitive sweep at 0.1 Hz throughout the drug perfusion to observe the compound effect over 42 sweeps. The normalized peak I Na inhibition was calculated using the following equation:

Equation

[0295] where I Reference is the average peak I Na density induced from the first 10 sweeps under perfusion with the Nanion standard external (reference) solution, and I Drugis the average peak I induced during the last 10 sweeps 3.5 minutes after vehicle, TTX, or XOB perfusion Na density. Peak I Na The quality control settings of the protocol were the same as the I-V protocol, except that the cell capacitance was <30 pF. To obtain the XOB concentration-response curve in Figure 2A, normalized peak I Na density inhibition data were fit by non-linear regression using the four-parameter variable slope inhibitor vs. response equation in GraphPad Prism. The data point for 1 pM XOB was set equal to the vehicle response, and 1 mM XOB was set equal to the response of 1 μM TTX.

[0296] Preparation of brain slices: Acute brain slices were prepared as previously described (Hull et al., Ann Clin Transl Neur., 2020;7(11):2137-2149). Briefly, mice were anesthetized by isoflurane anesthesia and decapitated. The brain was carefully removed from the skull and placed in ice-cold carbogenated slicing solution containing (in mM) 110 sucrose, 62.5 NaCl, 2.5 KCl, 6 MgCl2, 1.25 KH2PO4, 26 NaHCO3, 0.5 CaCl2, 20 D-glucose, pH 7.35-7.40. The brain was blocked and cut into 250-μm-thick coronal slices from the prefrontal cortex using a vibrating microtome (Electron Microscopy Sciences). Slices were incubated at room temperature for 30 minutes in a gassed holding chamber containing the solution and then incubated at 35 °C for 30 minutes in 1:1 slice:artificial cerebrospinal fluid (ACSF). ACSF contained (in mM) 125 NaCl; 2.5 KCl; 1 MgCl2; 1.25 KH2PO4; 26 NaHCO3; 2 CaCl2; and 20 D-glucose (pH 7.35-7.40). Slices were then gassed in a holding chamber containing 100% ACSF at room temperature for at least 30 minutes before recording.

[0297] Recording and analysis of action potentials: Individual brain slices were placed in an RC-26 recording chamber (Warner Instruments) and superfused with aerated ACSF at a flow rate of 2-3 mL / min with an in-line heater (Warner Instruments) to maintain the recording temperature at 33-35 °C. Layer 5 pyramidal neurons were identified based on their large soma size, shape, and position using an A1R upright confocal microscope (Nikon) equipped with an IR-DIC optical system and a 40x water immersion objective lens. Only vertically oriented pyramidal cells were selected for recording. The recording electrodes had a resistance of 4-8 MΩ in a solution containing (in mM) 140 K-gluconate, 4 NaCl, 0.5 CaCl2, 10 HEPES, 5 EGTA, 5 phosphocreatine, 2 Mg-ATP, and 0.4 GTP (pH 7.2-7.3 with KOH). The junction potential was calculated to be 14.3 mV using a P-clamp junction potential computer, and all values shown in the study were not corrected. After break-in at -94.3 mV in voltage-clamp mode, the resting membrane potential was defined as the membrane potential in current-clamp within <10 s after the first break-in relative to the baseline or immediately after XOB perfusion. Repetitive action potential firing was induced in whole-cell current-clamp from the resting membrane potential during 1 s long current injections in 10 pA steps from -20 pA to +400 pA. There was a 0 pA current injection of 1 s length between each sweep. Data were acquired at 20 kHz and filtered at 10 kHz. Cells with an access resistance measured at a voltage-clamp of >20 MΩ or a depolarized RMP exceeding -64.3 mV were not used. Access resistance and pipette capacitance were compensated using bridge balance. Whole-cell capacitance was measured using P-clamp whole-cell capacitance compensation in voltage-clamp with a depolarizing step from -94.3 mV to 10 mV. Automated quantification and analysis of action potentials (APs) were performed using custom MATLAB (MathWorks) software. APs were defined as the voltage crossing 0 mV after dV / dt > 10 mV / ms, which was here defined as the AP threshold. Input resistance was calculated using Ohm's law with a -10 pA current injection from the resting membrane potential 250 ms later.

[0298] 5-HT Receptor Binding Assay:

[0299] Ligand Binding Assay Based on NanoBRET: HEK293 cells expressing the HiBiT-tagged 5-HT receptor were treated with serial dilutions of the fluorescent tracer in the presence or absence of 30 μM of competing unmodified ligand. The plates were mixed briefly and incubated at room temperature for 90 minutes. To measure BRET, the cells were treated with 2× detection solution containing 100-fold diluted LgBiT (Promega) and 50-fold diluted furimazine live cell substrate (Promega) in Opti-MEM. The plates were mixed for 10 minutes to allow HiBiT / LgBiT complementation. Then, the filtered luminescence was measured using a GloMax Discover Microplate Reader (Promega) equipped with a 450 nm (8 nm bandpass) filter (donor) and a 600 nm longpass filter (acceptor). BRET was calculated by dividing the acceptor >600 nm light output by the donor 450 nm luminescence. Values were background corrected by subtracting the BRET value from samples treated with excess unmodified ligand.

[0300] For the competitive displacement experiment, cells were treated with serial dilutions of the unmodified ligand in the presence of a fixed EC 80 concentration of the fluorescent tracer. The plates were mixed briefly and incubated at room temperature for 90 minutes. Then, the cells were treated with 2× detection solution and BRET measurements were performed as described above. Affinity values (K I ) were calculated from the observed IC 50 values according to the Cheng-Prusoff equation (Cheng and Prusoff, Biochem Pharmacol., 1973;22(23):3099-3108).

[0301] Kinetic measurement of ligand binding to HiBiT-tagged 5-HT receptors: For the binding kinetics of the clozapine tracer, cells were treated with a 2× detection solution containing 100-fold diluted LgBiT (Promega) and 50-fold diluted furimazine live cell substrate (Promega) in phenol red-free Opti-MEM. To determine specific binding, control wells were also treated with a final concentration of 30 μM clozapine. After mixing the plates for 15 minutes, serially diluted clozapine tracer was added. After brief mixing, kinetic reads were immediately collected with a GloMax Discover Microplate Reader (Promega).

[0302] For the binding kinetics of unmodified ligands, cells were first treated with the 2× detection solution as above, and control wells were further treated with excess clozapine. After a 15-minute incubation, cells were treated with serially diluted unmodified ligand and a fixed EC80 concentration of clozapine tracer. After brief mixing, kinetic measurements were immediately collected with a GloMax Discover Microplate Reader (Promega).

[0303] Data analysis: Using GraphPad Prism software, saturation KD values were derived from a "one-site binding" fit, and competition IC 50 values were derived from a "log(inhibitor) vs. response variable slope" fit. The IC 50 values were then used to derive the binding affinity (KI) for the unmodified ligand according to the Cheng-Prusoff equation, where [L] is the concentration of the fluorescent ligand in the assay and KD is its affinity in the saturation binding experiment:

Equation

[0304] The kinetic analysis of the fluorescent tracer was graphed using association kinetics - hot fit for two or more concentrations. From the resulting curves, the rate constants (k on and k off) and the association constant (K D ) were determined (Tummino et al., Biochemistry-US., 2008:47(20):5481-5492). The kinetic analysis of the unmodified compound was graphed using the kinetics of competitive binding fitting (Motulsky-Mahan model for the kinetics of competitive binding) (Motulsky and Mahan, Mol Pharmacol., 1984;25(1):1-9). The binding affinity and other rate constants were determined from the resulting curves.

[0305] 5-HT Receptor Function Assay: The stably expressing 5-HT2 receptor Flp-In 293 T-Rex tetracycline-inducible system (Invitrogen, mycoplasma-free) was used for the calcium flux assay as previously described and utilized (Klein et al., ACS Pharmacol Transl Sci., 2021;4(2):533-542). The cell line was maintained in DMEM containing 10% FBS, 10 μg / mL blasticidin (Invivogen), and 100 μg / mL hygromycin B (GoldBio). The day before the assay, receptor expression was induced with tetracycline (2 μL / mL) and seeded at a density of 7,500 cells / well in a 384-well poly-L-lysine-coated black plate in DMEM containing 1% dialyzed FBS. On the day of the assay, the cells were incubated with Fluo-4 Direct dye (Invitrogen, 20 μl / well) for 1 hour at 37°C, which was reconstituted in drug buffer (20 mM HEPES-buffered HBSS, pH 7.4) containing 2.5 mM probenecid. After dye loading, the cells were equilibrated at room temperature for 15 minutes and then placed in a FLIPR TETRA fluorescence imaging plate reader (Molecular Devices). Drug dilutions were prepared at 5× the final concentration in drug buffer (20 mM HEPES-buffered HBSS, pH 7.4) supplemented with 0.3% BSA fatty acid-free and 0.03% ascorbic acid. The drug dilutions were dispensed into a 384-well plastic plate and placed in the FLIPR TETRA for drug stimulation. Fluorescence reads were programmed to record the baseline fluorescence for 10 seconds (1 read / second), after which 5 μl of drug was added per well and read for a total of 2 minutes (1 read / second). The fluorescence in each well was normalized to the average of the first 10 reads for the baseline fluorescence, and then the maximum fold peak increase was calculated. The peak was plotted as a function of drug concentration, and the data were normalized to the percent 5-HT stimulation. In the antagonist mode, the plate was challenged with 3.2 nM 5-HT to measure the calcium flux blockade response.Plot the data and perform non-linear regression using "log(agonist) vs. response" in GraphPad Prism 9 to obtain the Emax and EC. 50 Parameter estimates were obtained.

[0306] Results: The binding affinities of XOB and serotonin to the HiBiT-tagged receptor transiently expressed in HEK293 cells were 330 nM, 470 nM, and 120 nM for serotonin at the 5-HT 1A , 5-HT 2A and 5-HT 2C receptors, respectively, revealing K I values for serotonin, which were in general agreement with the reported values. The binding affinity for XOB was K 2A = 2.6 μM at the 5-HT I receptor, and K 1A > 10 μM at the 5-HT 2C and 5-HT I receptors, which was significantly lower (Figure 12A - 12D).

[0307] The binding affinities derived from the kinetic analysis were consistent with the affinities obtained from the saturation binding experiments, revealing moderate association rates and fast dissociation rates. We observed the binding of serotonin and XOB to HiBiT - 5-HT 80 for 30 minutes in the presence of a fixed EC 2A concentration of the clozapine tracer (Figure 14). The binding affinities derived from the kinetics were generally equivalent to those obtained from the equilibrium analysis, but at the same time, it became clear that the weak potency of XOB at 5-HT 2A was likely explained by its slow association rate, which was approximately 24 times slower than the association rate of serotonin.

[0308] To measure the functional activity at the 5-HT2 receptor, human 5-HT 2A , 5-HT 2B and 5-HT 2CA functional assay was performed to measure Gq-mediated calcium flux activity in the receptor (Figs. 15A-15C). XOB showed little or no agonist activity measurable at any of the 5-HT2 receptors up to a concentration of 10 μM. However, when XOB was tested in antagonist mode competing with 5-HT, XOB showed a low micromolar antagonistic effect at 5-HT 2A (IC 50 = 1.3 μM), which was similar to the measured affinity (K I = 2-3 μM) values obtained using NanoBRET. However, XOB was not as potent in blocking the 5-HT-mediated calcium flux response at the 5-HT 2B and 5-HT 2C receptors, resulting in <50% inhibition at concentrations up to 10 μM, and thus showing 5-HT 2A antagonist selectivity for the closely related 5-HT2 receptors.

[0309] Inhibition of Nav1.1-generated sodium currents by XOB using manual and automated patch-clamp: Investigation of the modulation of VGSC function by XOB was initiated with an initial analysis of 10 μM XOB on I v mediated by human Na Na 1.1 stably expressed in HEK cells using manual whole-cell patch-clamp (Fig. 16A). In three cells, acute perfusion with 10 μM XOB decreased the mean Na v 1.1 peak I Na density by 94.1 ± 1.31% compared to the baseline at 0 mV. The acute inhibition of Na v 1.1 by XOB was prolonged, and only 17.5 ± 3.64% of the original baseline I Na density at 0 mV recovered 10 minutes after washout of XOB. The inhibitory effect of 10 μM XOB on the current-voltage (I-V) relationship of Na v 1.1 is shown in (Fig. 16B). Next, the inventors investigated human Na vWe investigated whether co-expression of the β1 subunit (O'Malley, Annu Rev Physiol., 2015;77:481-504) altered the acute inhibitory effect of XOB at concentrations of 10 μM, 5 μM, and 1 μM (Figure 16C). After 3.9 min of perfusion, 10 μM and 5 μM XOB reduced Na v 1.1 Peak I Na 1 μM XOB reduced Na by 98.6% and 95.7%. v 1.1 Peak I Na 35.3% (Table 6). Acute I in cells expressing hNav1.1+hb1 at 10, 5 and 1 μM XOB Na A diary plot showing the perfusion time course of inhibition is shown in (FIG. 16D). [Table 8]

[0310] I Na To efficiently characterize the concentration-response relationship for XOB-mediated inhibition of hNa, we used high-throughput automated patch clamp technology (Nanion SyncroPatch 384) to measure the concentration-response relationship for XOB-mediated inhibition of hNa. v Recorded from HEK cells expressing 1.1+hb1. Peak I Na The concentration response curve of XOB to β-lactamase showed an IC of 4.29 μM. 50 At 10 μM, XOB produced a baseline peak I Na Peak I was reduced by 73±3%. Na This level of inhibition is similar to that of 1 μM TTX, and is the peak I Na Vehicle (0.1% EtOH), 1 μM TTX, or increasing concentrations of XOB reduced Na v 1.1 Peak I Na A heat map showing the relative levels of inhibition is shown in (Figure 17B). Representative peak I using a protocol stepping from -120 mV to -10 mV in the presence of vehicle, 10 μM XOB or 1 μM TTX. NaThe trace is shown in (Figure 17C). All recorded peak Is under baseline and drug conditions Na The mean peak I of each concentration group of cells in the sweep Na Values are shown in (Figure 17D).

Table 9

[0311] Peak I of XOB Na To further investigate the mechanism of the decrease of, the inventors performed a protocol to induce the I-V relationship and examined whether XOB regulates the voltage-dependent properties of Na v 1.1 + b1 I Na The I-V curves in the presence of vehicle, 1 μM TTX, or increasing concentrations of XOB are shown in (Figure 18A and Table 8). The corresponding peak I Na densities at the -20 mV step of the I-V curve are shown in (Figure 18B). As expected from the manual patch-clamp experiments, all cell groups perfused with 3, 5, or 10 μM XOB showed a significant inhibition of peak I Na density at -20 mV compared to vehicle (3 μM: P = 0.0019; 5 μM: P = 0.0002; 10 μM: P < 0.0001; one-way ANOVA, see Table 10). Equivalent levels of peak I Na densities were observed in cell groups perfused with 1 μM TTX (-15.84 ± 2.16 pA / pF) and 10 μM XOB (-17.46 ± 3.1 pA / pF). When analyzing the voltage-dependence of sodium conductance, no effect was observed. However, perfusion with 3 μM XOB induced a significant -5.7 mV shift in the voltage-dependence of I Na availability (P value: 0.023; unpaired t-test, see Figure 18C and Table 9). This hyperpolarization shift in the voltage-dependence of inactivation is likely to contribute to the inhibitory effect of XOB on Na v 1.1.

Table 10

Table 11

[0312] Acute effects of 10 μM XOB on pyramidal neurons in layer V of the mouse prefrontal cortex

[0313] Na in HEK cells v After characterizing the effects of XOB at various concentrations on the 1.1 + b1 function, the inventors examined whether this observed inhibition of the major neuronal sodium channel subtypes in the heterologous system would translate to an in vivo model. Accordingly, the inventors recorded the passive and active properties of layer V pyramidal neurons in slices of the prefrontal cortex (PFC) of wild-type mice (Figure 19). Acute perfusion with 10 μM XOB decreased the maximum firing frequency of PFC layer V pyramidal neurons by approximately 12 Hz with 400 pA current injection (baseline = 24.88 ± 2.07 Hz; 10 μM XOB = 14 ± 1.82 Hz). 10 μM XOB induced a depolarization of +8.45 ± 1.15 mV of the resting membrane potential (baseline = -71.7 ± 1.04 mV vs. 10 μM XOB = -63.25 ± 1.15 mV), the peak amplitude of the first AP (baseline = 47.4 ± 1.42 mV vs. 10 μM XOB = 41.21 ± 2.92 mV), the maximum dV / dt (baseline = 471.73 ± 27.12 mV / ms vs. 10 μM XOB = 402.68 ± 46.20 mV / ms), the minimum dV / dt (baseline = -103 ± 6.28 mV / ms vs. 10 μM XOB = -91.32 ± 8.95 mV / ms), and the threshold of the first AP (baseline = -42.84 ± 1.02 mV vs. 10 μM XOB = -38.43 ± 1.23 mV) significantly. After perfusion with 10 μM XOB, no significant changes in input resistance (baseline = 104.52 ± 21.84 MΩ vs. 10 μM XOB = 100.08 ± 30.18 MΩ) or spike width (baseline = 0.72 ± 0.02 ms vs. 10 μM XOB = 0.76 ± 0.06 ms) were observed (see Figures 19A - 19J and Table 11). [Table 12]

Table 13

[0314] Investigation: Tryptamine-class psychedelic compounds such as psilocin and DMT are resurfacing as promising therapeutic candidates for treating a number of psychiatric conditions, including depression, substance use, and anxiety-related disorders (Vollenweider and Preller, Nat Rev Neurosci, 2020;21(11):611-624; D’Souza et al., Neuropsychopharmacol., 2022;47(10):1854-1862).

[0315] Phenylalkylamine psychedelic drugs such as 2C-B also have clinically desirable properties such as oral activity at 12 - 24 mg, low sympathetic stimulatory effects, and a moderate duration of action of 4 - 8 hours (Shulgin and Carter, Psychopharmacol Commun., 1975;1(1):93-98; Papaseit et al., Front Pharmacol., 2018;9:206), and there are preliminary signs of effectiveness in psychiatric conditions (Gonzalez et al., Biomed Res Int., 2015;2015). In vitro tests using [I]-2,5-dimethoxy-4-iodoamphetamine ( 2A ([I]-DOI) competitive binding in heterologous cells expressing human or rat 5-HT 125 receptors have reported high affinity for 2C-B with K 125 values of 0.88 nM and 0.66 nM, respectively (McLean et al., J Med Chem., 2006;49(19):5794-5803). Functionally, 2C-B is a 5-HT I mobilization assay-measured 5-HT 2+ (EC 2A = 2.1 nM), 5-HT 50 (EC 2B = 57 nM) and 5-HT 50 (EC 2C = 5-HT50 shows high potency for the receptor (= 43 nM) (Luethi et al., Neuropharmacol., 2018; 134: 141 - 148). 5-HT 2A 2C - B, which shows high affinity and potency at the 5-HT q receptor, acts as a partial agonist with a widely variable efficacy in PLC binding, PLA2 binding, and G 2+ coupled Ca 2A mediated assays (McLean et al., J Med Chem., 2006; 49(19): 5794 - 5803; Moya et al., J Pharmacol Exp Ther., 2007; 321(3): 1054 - 1061; Rickli et al., Neuropharmacol., 2015; 99: 546 - 553; Luethi et al., Neuropharmacol., 2018; 134: 141 - 148). Interestingly, 2C - B 2A acts as an antagonist in 5-HT 2A mediated inward current recordings from Xenopus oocytes transiently expressing the 5-HT 2+ receptor (Acuna - Castillo et al., Br J Pharmacol., 2002; 136(4): 510 - 519; Villalobos et al., Br J Pharmacol., 2004; 21(11): 611 - 624). The responses generated in the oocyte model are likely to represent chloride currents generated by transiently overexpressed 5-HT

[0316] In this study, the inventors attempted to investigate the chemical space of 2C-B binding at serotonin receptors by synthesizing the extended side-chain compound XOB as a probe for a putative exosite similar to the adrenergic β2 receptor exosite (McCorvy et al., Nat Struct Mol Biol., 2018;25(9):787-796; Kim et al., Cell, 2020;182(6):1574-1588). The inventors hypothesized that the aralkyloxyalkyl side chain enhances affinity and slows the rate of XOB binding at the 5-HT 2A receptor compared to the parent 2C-B molecule. XOB showed a much slower association rate but decreased affinity for the 5-HT 2A receptor compared to 2C-B, and very low binding to the 5-HT 2B 、5-HT 2C 、and 5-HT 1A receptors. Functionally, XOB shows some selective antagonism at the 5-HT 2A receptor (Figs. 15A-15C).

[0317] Rather than enhancing the interaction of XOB with the putative 5-HT 2A receptor exosite, the extension of the aralkyloxyalkyl side chain on XOB may increase non-specific interactions with the lipid bilayer or another membrane protein. The unexpected finding of VGSC inhibition by XOB supports off-target binding of XOB to another membrane protein. At low micromolar concentrations, XOB significantly decreased peak I Na density and hyperpolarized the voltage dependence of I Na fast inactivation (Figs. 17A-17D). Initial experiments using manual patch-clamp showed that XOB inhibits the I v produced by hNa Na 1.1+hb1 in HEK cells. The lack of recovery of I Na after washout of XOB is consistent with its slow association rate and lipophilic properties of the molecule observed in our serotonin receptor binding kinetics analysis. I NaTo better understand the scope of XOB inhibition, the inventors used high-throughput patch-clamp technology. The inventors observed concentration-dependent inhibition of Na v 1.1 + b1 generating I Na by XOB at 4.29 μM IC 50 which is comparable to the affinity (K 2A = 2.6 μM) and efficacy (IC I = 1.3 μM) of XOB at the 5-HT 50 receptor. In addition to blocking peak I Na XOB affected the voltage-dependent gating of Na v 1.1. XOB did not significantly affect the voltage-dependence of activation, but 3 μM XOB caused a significant hyperpolarizing shift in the voltage-dependence of I Na fast inactivation. This shift in the voltage-dependence of availability provides mechanistic insight into the inhibitory action of XOB on VGSCs. In the presence of XOB, more VGSCs in the brain are inactivated or made unavailable at hyperpolarized membrane potentials. This shift is expected to decrease the window current, raise the AP threshold, and ultimately reduce the intrinsic excitability of neurons in the presence of XOB.

[0318] Indeed, acute perfusion with 10 μM XOB significantly decreased the maximum AP firing frequency, AP peak amplitude, AP depolarization and repolarization rates (dV / dt), and depolarized the resting membrane potential and AP threshold of mouse PFC layer V pyramidal neurons in brain slices (Figs. 19A - 19J, Fig. 20). Particularly prominent expression of 5-HT 2A receptors is seen in cortical layer V pyramidal neurons where they are concentrated in the apical dendritic compartment (Willins et al., Synapse, 1997; 27(1):79 - 82; Jakab and Goldman-Rakic, Proc Natl Acad Sci USA, 1998; 95(2):735 - 740; Weber and Andrade, Front Neurosci, 2010; 4:36). 5-HT 2A receptor activation on layer V pyramidal neurons generally, probably via Gα qis thought to be excitatory via the conjugate pathway (making the cell more prone to spiking), while 5-HT 1A receptors are thought to inhibit pyramidal neurons via the activation of G protein-coupled inward rectifier K + channels (GIRK) (Araneda and Andrade, Neuroscience, 1991;40(2):399-412; Andrade, Ann NY Acad Sci., 1998;861(1):190-203; Andrade, Neuropharmacol., 2011:61(3):382-386). Through the dual antagonistic effects on 5-HT 2A receptors and VGSCs, the inventors hypothesized that XOB has an inhibitory effect on the excitability of PFC layer V pyramidal neurons. The inventors believe that the significant decrease in the AP firing frequency, peak amplitude, and the rates of depolarization and repolarization of PFC layer V pyramidal neurons by XOB is due to the inhibition of VGSCs. Based on the excitatory effects of the proposed 5-HT 2A agonist, the inventors predicted that the 5-HT 2A antagonistic effect of XOB would result in either no change or hyperpolarization of the resting membrane potential. The significant depolarization of the resting membrane potential presents doubts about this prediction and what is expected from classical VGSC blockers, raising the possibility that XOB regulates other ion conductances that contribute to the resting membrane potential. The lack of a significant change in input resistance raises the possibility that other ion channels are open in response to XOB, masking the expected change in input resistance caused by VGSC inhibition. Although no significant change in spike half-width indicating the regulation of other voltage-dependent conductances was observed after XOB perfusion, it is also possible that the VGSC inhibition by XOB had a negligible effect on the membrane potential and input resistance when measured at rest, when most of the VGSCs in the neuron would be in a non-conducting state.

[0319] 5-HT 2A Future analysis of the acute effects of XOB in layer V pyramidal neurons from 5-HT 2Aand VGSC antagonism will help to isolate the contribution of XOB to the suppression of excitability. It is important to note that the mice used in this study were young (about 3 weeks old), and when interpreting the effects of XOB on neuronal excitability, neurodevelopmental factors including the age-dependence of 5-HT receptor expression in rodent cortex should be considered (Beique et al., J Neurosci., 2004;24(20):4807-4817). Furthermore, neurons recorded from the medial PFC were not further differentiated into the prelimbic, infralimbic, and anterior cingulate cortices. Thus, regional specific differences in the effects of XOB on mPFC neurons may have been unclear in this study. Another limitation of these physiological data is the difference in 5-HT 2A receptor amino acid sequences between humans and rodent species. Although highly conserved, the divergent regions between humans and rodents can affect the functional interactions of ligands that bind to 5-HT 2A receptors (Dougherty and Aloyo, Psychopharmacol(Berl), 2011;215(3):581-593). The use of humanized 5-HT 2A receptor transgenic rodent models may be more physiologically appropriate in future slice physiology studies.

[0320] XOB shows negligible binding affinity at 5-HT 1A receptors and shows selectivity for 5-HT 2B over 5-HT 2C and 5-HT 2A receptors. Therefore, the inventors believe that the serotonergic component of its effect on the intrinsic excitability of layer V pyramidal neurons is due to 5-HT 2A antagonism. In addition to endogenous regulation, 5-HT 2A receptors may affect neuronal excitability via circuit-level synaptic effects that were not measured in the inventors' current clamp experiments using XOB. 5-HT 2AIt is well established that agonists increase the frequency of excitatory postsynaptic potentials and currents, particularly asynchronous (non-electrically evoked) release in layer V pyramidal neurons of the PFC (Aghajanian and Marek, Neuropharmacol., 1997; 36(4-5):589-599; Aghajanian and Marek, Brain Res., 1999; 825(1-2):161-171; Marek and Aghajanian, Eur J Pharmacol., 1999; 367(2-3):197-206; Andrade, Ann NY Acad Sci., 1998; 861(1):190-203; Andrade, Neuropharmacol., 2011:61(3):382-386). Psychedelic 5-HT such as DOI 2A In the presence of an agonist, it is expected that XOB will significantly decrease the amplitude and frequency of EPSC in layer V pyramidal neurons. 5-HT 2A Receptors are also expressed on cortical GABAergic interneurons (Willins et al., Synapse, 1997; 27(1):79-82; Jakab and Goldman-Rakic, Proc Natl Acad Sci USA, 1998; 95(2):735-740; Santana et al., Cereb Cortex., 2004; 14(10):1100-1109). Na v Since Na1.1 is mainly considered to be localized in the axonal initial segment of parvalbumin-positive (PV+) GABAergic fast-spiking interneurons in the cortex, it is expected that XOB will reduce the excitability of cortical PV+ interneurons (Ogiwara et al., J Neurosci., 2007; 27(22):5903-5914). Future evaluation of the effects of XOB on GABAergic interneurons as well as other isolated VGSC subtypes would be beneficial.

[0321] Clinically effective drugs used in the treatment of schizophrenia and bipolar disorder are 5-HT respectively 2AShow significant antagonist (or inverse agonist) activity at receptors (e.g., risperidone, clozapine) and VGSCs (e.g., carbamazepine, lamotrigine), and these targets are considered important contributing factors to their therapeutic effects. Pharmacologically, atypical antipsychotics are associated with dual antagonism at D2 receptors and 5-HT 2A receptors (Stahl, Antipsychotics and mood stabilizers: Stahl’s essential psychopharmacology. Cambridge University Press. 2008). Furthermore, 5-HT 2A antagonism is hypothesized to improve negative symptoms and reduce the harmful extrapyramidal symptoms often observed in antipsychotic treatment (Meltzer, Neuropsychopharmacol, 1999;25(1):1-9). Targeted sequencing of large patient populations has implicated VGSCs in the pathophysiology of schizophrenia (Rees et al., Biol Psychiatry., 2019;85(7):554-562). Furthermore, adjunctive lamotrigine therapy has shown efficacy in the treatment of schizophrenia, presumably through modulation of cortical excitability and glutamate transmission (Large et al., Psychopharmacol., 2005;181:415-436). Together, these findings highlight the strong translational value of XOB as a novel class that acts at 5-HT 2A receptors and VGSCs.

[0322] In summary, the inventors report the discovery of a new structural class of substituted phenylalkylamines that antagonize both 5-HT 2A receptors and VGSCs, two important molecular actions for psychiatric treatment. As a therapeutic lead, XOB offers an advance for the development of more targeted psychiatric therapeutics with reduced adverse effects. As a tool, XOB is useful for studying the role of 5-HT 2AIt has the potential to advance the understanding of the complex contributions of receptors and VGSCs. Further characterization and structure optimization may be beneficial, but XOB is a good starting point for further exploration in chemical neuroscience and biological psychiatry.

[0323] Example 4 Synthesis of the disclosed N-substituted phenylalkylamine compounds Further N-substituted phenylalkylamines, such as compounds of formula (I) or (II), can be synthesized according to the general reaction sequence shown in Scheme 2.

Chemical formula

[0324] Scheme 2. General synthesis of compounds of formula (I) and (II) Briefly, an appropriate phenylalkylamine precursor is reacted with a side chain precursor (e.g., Br(CH2) as shown above) under condensation conditions by nucleophilic substitution of a leaving group (in this exemplary case, bromide) by a phenylalkylamine amine to produce a compound of formula (I) or (II). m X(CH2) n Ph) to produce a compound of formula (I) or (II).

[0325] In this example, potassium iodide is used to facilitate the nucleophilic substitution reaction. The addition of an inorganic iodide salt (e.g., potassium iodide, sodium iodide) to improve the efficiency of the nucleophilic substitution reaction is a well-known technique. However, potassium iodide is not necessary for the reaction to proceed. One of ordinary skill in the art can determine whether potassium iodide should be added and, if so, how much to use.

[0326] In this example, triethylamine is used as the exemplary base. However, as will be understood by those skilled in the art, other bases may be used. For example, diisopropylethylamine (DIPEA) and pyridine are common organic bases. Similarly, although acetonitrile is shown as the exemplary solvent, replacing acetonitrile with another suitable solvent can be done according to the knowledge of those skilled in the art.

[0327] The synthesis of any other necessary starting materials or reagents will be readily apparent to those skilled in the art in view of the present disclosure in conjunction with general references well known in the art. (For example, all of them, in combination with the disclosure of this specification, can be used to synthesize the compounds of the present invention, Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed. 1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-17, Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Volumes 1-45, Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience, 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995; Glennon et al. 1986. J. Med. Chem., 29(2), 194-199; Nichols et al. 1991. J. Med. Chem., 34(1), 276-281; Kedrowski et al. 2007. Organic Letters, 9(17), 3205-3207; Heravi & Zadsirjan. 2016.See Current Organic Synthesis, 13(6), 780 - 833; Keri et al. 2017. European J. Med. Chem., 138, 1002 - 1033; Perez - Silanes et al. 2001. J. Heterocyclic Chem, 38(5), 1025 - 1030), as well as European Patent No. 1937626 (U.S. Patent No. 8648214) which describes the synthesis of salmeterol and its analogs.

[0328] Example 5 Synthesis of N - substituted phenylalkylamine analogs with mutant side chains Objective: To synthesize and physically characterize novel N - substituted analogs of phenylalkylamines with isomeric side chains.

[0329] Method: To further probe the extended binding sites of the 5 - HT 2A , 5 - HT 2B , and 5 - HT 2C receptors, the position of the heteroatom "hinge" in the analog series is moved along the methylene unit to create isomeric side - chain mutants. For example, in the case of a 10 - carbon side chain, the "1 and 9", "2 and 8", "3 and 7", "4 and 6", "5 and 5", "7 and 3", "8 and 2", or "9 and 1" mutants, as well as "oxygen - free" compounds containing only methylene units, are synthesized and compared (see Table 1). Such compounds are synthesized according to Examples 1 and 4 and the above - mentioned considerations associated therewith, in which the exemplary "6 and 4" side chain is replaced with "1 and 9", "2 and 8", "3 and 7", "4 and 6", "5 and 5", "7 and 3", "8 and 2", or "9 and 1" mutants, as well as "oxygen - free" side chains containing only methylene units. A series of N - substituted phenylalkylamines according to formula (I) or (II) are also synthesized. In other examples, phenylalkylamine 5 - HT 2A receptor ligands, such as 2C - I, 2C - E, 2C - T, mescaline, and others known to those skilled in the art, can be modified according to the described methods.

[0330] Results: Specific reaction conditions and isolation procedures are determined empirically for each target compound. The novel compounds are physically characterized by thermal analysis, proton and carbon nuclear magnetic resonance spectroscopy ( 1 H NMR, 13 C NMR), GC-MS, LC-MS, X-ray diffraction, as well as elemental analysis. The described syntheses, which are straightforward and utilize chemistry known to those skilled in the art, are expected to produce novel N-substituted phenethylamine compounds. Such compounds may exhibit improved properties such as enhanced binding affinity, specificity, or duration of action.

[0331] Example 6 Evaluation of the in vitro pharmacological activity of the disclosed compounds Purpose: To characterize the binding profiles and functional activities of the disclosed compounds at various receptors, channels, and transporters, receptor screening is performed. The results facilitate comparison with unsubstituted phenylalkylamines and other psychedelic drugs. Furthermore, the data are used to support or modify the primary exosite hypothesis, and the structure-activity analysis of the data will be useful in the design of new compounds.

[0332] Methods: The disclosed compounds are synthesized and submitted to the Psychoactive Drug Screening Program (PDSP), which is funded by the National Institute of Mental Health. PDSP screening includes evaluation at 45 receptor and transporter binding sites. Most of the screening is performed using cloned human receptors, with some exceptions. See, for example, the PDSP screening and results for DALT and its derivatives (Cozzi & Daley, Bioorganic & Medicinal Chemistry Letters, 2016; 26(3):959-964; Klein et al., Neuropharmacology, 2018; 142:231-239).

[0333] Briefly, the test compound is dissolved in DMSO and tested at 10 mM in a competitive assay against a radioactive probe compound. Sites showing >50% inhibition at 10 mM are tested in a secondary assay at the identified receptor or transporter using 12 concentrations of the test compound measured in triplicate to generate a competitive binding isotherm. K i values are obtained by non-linear regression of these binding isotherms from the best fit IC 50 values using the Cheng-Prusoff equation (Cheng & Prusoff, Biochem Pharmacol., 1973;22(23):3099-108). For data analysis and comparison, K i values are converted to pK i (-log K i ) values.

[0334] Binding assays are performed using the following radioactive ligands: 3 [3H]8-OH-DPAT (5-HT 1A ), 3 [3H]GR125743 (5-HT 1B / 1D ), 3 [3H]5-HT (5-HT 1E ), 3 [3H]ketanserin (5-HT 2A ), 3 [3H]LSD (5-HT 2A / 2B / 6 / 7 ), [3H]methysergide (5-HT 2C ), 3 [3H]citalopram (serotonin transporter), 3 [3H]prazosin (α1A / 1B / 1D), 3 [3H]rauwolscine (α2, 5-HT 2A / 2B ), 125 [125I]pindolol (b1), 3 [3H]CGP12177 (b2, b3), 3 [3H]nisoxetine (norepinephrine transporter), 3 [3H]SCH23390 (D1, D5), [ 3 [3H]N-methylspiperone (D2 / 3 / 4), 3 [3H]WIN35428 (dopamine transporter), 3 ​H]DAMGO (μ-opioid), 3 H]DADLE (δ-opioid), 3 H]U69593 (κ-opioid), 3 H]Muscimol (GABA A ), 3 H]Flunitrazepam (central benzodiazepine), 3 H]PK11195 (peripheral benzodiazepine), 3 H]Pyrilamine (H1), 3 H]Thiothixene (H2), 3 H]α-Methylhistamine (H3), 3 H]Histamine (H4), 3 H]QNB (M1e5), 3 H](t)-Pentazocine (s1), and 3 H]DTG (s2).

[0335] The experimental protocol is available from the NIMH PDSP website, e.g., “Assay Protocol Book, Version III, March 2018, Bryan L. Roth, MD, PhD.” Briefly, both primary and secondary radioligand binding assays are performed in appropriate binding buffer. The hot ligand concentration is on the order of K d and the same. Total binding and non-specific binding are determined in the absence and presence of 10 μM of an appropriate reference compound, respectively. The plates are incubated for 90 minutes at room temperature and in the dark. The reaction is stopped by vacuum filtration onto a 96-well filtermat soaked in 0.3% polyethyleneimine (PEI) using a 96-well Filtermate harvester, followed by washing three times with cold wash buffer. The scintillation cocktail is then melted onto the microwave-dried filter in a hot plate and radioactivity is counted in a Microbeta counter.

[0336] Results: The disclosed compounds are 5-HT based on the head groups of psychedelic lead compounds 2AIt is expected to show affinity for the receptor. However, when evaluated in view of the teachings herein, the side chain is 5-HT in a manner understood to be similar to the binding of XOB 2A If it interacts with the receptor exosite, it is expected that the binding affinity and binding efficacy will change.

[0337] Example 7 Metabolic stability Objective: To determine the metabolic stability of the disclosed compounds. The metabolic stability assay measures the intrinsic clearance (CL int ) of the compound and provides data that can be used to calculate other important pharmacokinetic parameters such as bioavailability and half-life (t 1 / 2 ).

[0338] Method: Using LCMS analysis to quantify the percentage of the compound remaining after incubation, the metabolic stability of the disclosed compounds and their non-deuterated analogs in various matrices containing human liver microsomes is determined using a high-throughput assay. Briefly, the disclosed compound is mixed with liver microsomes and activated. After this incubation, acetonitrile is added to stop the reaction. The sample is then centrifuged and the supernatant is dried. The residue is reconstituted and analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters are calculated using a non-compartmental model. The half-life (t 1 / 2 ) is estimated from the slope of the initial linear range of the logarithm of the residual compound (%) versus time, assuming first-order kinetics.

[0339] Results and significance: The disclosed compounds may have altered clearance and half-life compared to comparators such as the corresponding unsubstituted phenethylamine. Such characteristics provide advantages such as an extended or shortened duration of action that facilitate use in the therapeutic applications described herein.

[0340] Example 8 In vitro metabolic profiling Objective: To determine whether the disclosed compound is metabolized and to identify its metabolites.

[0341] Method: An in vitro test is conducted to evaluate the metabolism of the disclosed compound and its metabolites in human liver microsomes such as S9 hepatocytes. Briefly, the disclosed compound is incubated with human liver microsomes and / or various recombinant enzymes to determine metabolism and metabolite formation. After incubation, the supernatant is directly analyzed by ultra-high performance liquid chromatography-mass spectrometry.

[0342] Mass spectrometry (MS) is used to identify phase I and / or phase II metabolites. The residual compound % and half-life of the disclosed compound (parent compound) are determined. MS data such as extracted ion chromatograms show the parent and major metabolites. Elucidate the metabolic transformation of each observed metabolite and determine the mass, peak area, and retention time of the metabolite. Metabolic profiling can also be performed according to the methods described in Muller & Rentsch, Anal Bioanal Chem, 2012; 402: 2141-2151 and Pedersen et al., Drug Metab Dispos, 2013; 41: 1247-1255.

[0343] Results and Significance: Compounds that are metabolized in vivo can produce pharmacologically active or chemically reactive metabolites that cause unexpected effects or potential toxicity. The FDA Guidance for Industry on Safety Testing of Drug Metabolites emphasizes the validity of in vitro metabolite profiling in the early stages of drug development because metabolites that are unique to humans or disproportionate in humans may require further toxicity testing.

[0344] Example 9 In Vitro CYP Enzyme Inhibition Objective: To evaluate the interaction between the disclosed compounds and cytochrome P450 (CYP450) enzymes. Such interactions can provide insights into metabolism-mediated drug-drug interactions that can occur when a compound affects the pharmacokinetics of a co-administered drug, such as absorption, distribution, metabolism, and excretion, by changing the activity of drug-metabolizing enzymes and / or drug transporters.

[0345] Methods: In vitro tests are performed to evaluate the inhibitory effect of the disclosed compounds on recombinant human CYP450 isoenzymes. Recombinant human CYP450 isoenzymes are used to metabolize a fluorogenic probe substrate to a fluorescent product. Inhibition of human P450 isoforms is measured by a decrease in fluorescence after treatment with various concentrations of the disclosed compounds.

[0346] Briefly, the disclosed compounds are incubated at different concentrations in a mixture containing buffer, enzyme, and substrate. Fluorescence is then measured using a plate reader, and the percentage inhibition can be extrapolated from the readings. Alternatively, the inhibitory effect of the disclosed compounds on CYP enzymes can be evaluated using high-performance liquid chromatography. Inhibition is evaluated using the Michaelis-Menten method. CYP enzyme inhibition can be performed according to the methods described in Lin et al., J Pharm Sci. 2007 Sep;96(9):2485-95 and Wojcikowski et al., Pharmacol Rep. 2020 Jun;72(3):612-621.

[0347] Results and significance: Metabolic enzymes in the liver, such as CYP450 enzymes, are responsible for most of the drug metabolism that occurs in the body. Six classes of CYP450 enzymes metabolize 90% of drugs, and two of the most important metabolic factors are CYP3A4 and CYP2D6 (Lynch & Price, Am Fam Physician. 2007;76(3):391-6). Compounds can interact with such enzymes by inhibiting their enzyme activity (CYP inhibition) or inducing their gene expression (CYP induction).

[0348] Example 10 In Vitro Evaluation of Membrane Permeability and Interaction with P-Glycoprotein (P-gp) in MDCKII MDR1 Cells Objective: To evaluate the permeability and transport liability of the disclosed compounds. Permeability was evaluated using MDCK (Madin-Darby canine kidney) cells, and the effect of P-glycoprotein (P-gp) was evaluated to determine drug transport.

[0349] Methods: To evaluate the apparent permeability of the disclosed compounds, bidirectional permeability tests (from apical to basolateral [AB] and from basolateral to apical [BA]) were performed. Additionally, an evaluation was conducted to determine whether the disclosed compounds act as P-gp substrates in MDCKII-MDR1 and mock MDCKII cell lines.

[0350] Briefly, the disclosed compounds and reference compounds were evaluated in two directions in the absence and presence of a P-gp inhibitor. MDCKII and MDCKII-MDR1 cells were incubated in transport buffer on both the apical [A] and basolateral [B] sides. Then, the disclosed compounds were added to each side of the cells and incubated. The transport rate of the disclosed compounds was determined in the absence or presence of a P-gp inhibitor. After incubation, if the disclosed compounds permeate the cells in both the AB and BA directions, the permeability of the cells was measured using an LC MS / MS system. The efflux ratio of the disclosed compounds was calculated to determine whether they are P-gp substrates.

[0351] Results and Significance: This screening provides insights into the movement of the disclosed compounds in biological systems. Compounds are classified as follows (Cambridge MedChem Consulting, ADME, 2019):

Table 14

[0352] The mass balance as a percentage (%) is calculated using the following formula. Recovery rate % = 100×(CD(t) + CR(t)) / C0

[0353] Here, CD(t) is the measured concentration in the donor well at time t (expressed as an IS ratio), CR(t) is the measured concentration in the receiver well at time t (expressed as an IS ratio), and C0 is the initial concentration in the donor solution (expressed as an IS ratio).

[0354] The percentage of cell integrity is calculated using the following formula: Integrity % = 100x[1 - RFU basal side / RFU apical side]

[0355] The LY RFU value is normalized by the background average value. If the efflux ratio in the absence of the inhibitor is >2 and the ratio is significantly decreased in the presence of the P-gp inhibitor, the test item is considered a P-gp substrate.

[0356] The foregoing description uses specific nomenclature for purposes of explanation to provide a complete understanding of the invention. However, it will be apparent to those skilled in the art that no specific details are required to practice the invention. Accordingly, the foregoing description of specific embodiments of the invention is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teachings. The embodiments are chosen and described in order to best explain the principles of the invention and its practical application, thereby enabling others skilled in the art to best utilize the invention and various embodiments with various modifications suitable for the particular uses contemplated, when such uses are disclosed beyond the specific examples presented. Accordingly, the scope of the invention is to be defined only by the following claims and their equivalents.

Claims

Claim 1 Formula (II): 【Chemical 1】 Wherein m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is O, S or NH; R and R2 are each independently C1-C8 alkoxy, and each C1-C8 alkoxy may be substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R1 is selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl or heterocyclyl, and each of these may be substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate; R3 is hydrogen or C1-C8 alkyl; and Ph is phenyl which may be substituted by halogen, azide, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano or nitrate) a compound, or a pharmaceutically acceptable salt thereof. Claim 2 wherein both R and R2 are -OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein both R and R2 are -OCH Claim 3 R3 is hydrogen, -CH ３ or -CH ２ CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is as defined above. Claim 4 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is F, Cl, Br or I. Claim 5 The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R1 is Br. Claim 6 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C8 alkyl. Claim 7 R1 is -CH ３ or -CH ２ CH ３ The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R1 is -CH Claim 8 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C8 thioalkyl.

9. R1 is -SCH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -SCH

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted phenyl.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl substituted with azide or C1-C8 alkoxy.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the sum of m + n is 8 to 12.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the sum of m + n is 9 to 11.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the sum of m + n is 10.

16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein m is 6 and n is 4.

17. A compound selected from Table 4, or a pharmaceutically acceptable salt thereof.

18. 【Table 1】 Or a pharmaceutically acceptable salt thereof.

19. 【Chemical Formula 2】 The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

21. The pharmaceutical composition according to claim 20, which is suitable for oral, buccal, sublingual, intranasal, injection, subcutaneous, intravenous or transdermal administration.

22. The pharmaceutical composition according to claim 21, which is in unit dosage form.

23. The pharmaceutical composition according to claim 22, wherein the unit dosage form contains the compound or a pharmaceutically acceptable salt thereof in a total amount of about 1 to about 500 mg, about 2.5 to about 250 mg, or about 5 to about 125 mg.

24. The pharmaceutical composition according to claim 23, which is an immediate release formulation, a controlled release formulation, a sustained release formulation, a slow release formulation, or a modified release formulation.

25. The pharmaceutical composition according to claim 20, which further comprises a therapeutically effective amount of a further active compound or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition according to claim 25, wherein the further active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathic agents and anti-nociceptive agents, anti-migraine agents, anti-anxiety agents, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anti-cancer agents, anti-emetics, appetite stimulants, anti-ulcer agents, antihistamines, antihypertensive agents, anti-spasmodics, anti-epileptic agents, bronchodilators, neuroprotective agents, nootropics, empathogens, psychedelic drugs, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, and vitamins, or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition according to claim 25, wherein the further active compound or a pharmaceutically acceptable salt thereof acts to increase a therapeutic effect, provide a further therapeutic effect, reduce an undesirable effect, increase stability or shelf life, improve bioavailability, induce a synergistic effect, or alter pharmacokinetics or pharmacodynamics.

28. The pharmaceutical composition according to claim 27, wherein the further therapeutic effect is an antioxidant effect, an anti-inflammatory effect, an analgesic effect, an anti-neuropathic effect, an anti-nociceptive effect, an anti-migraine effect, an anti-anxiety effect, an antidepressant effect, an antipsychotic effect, an anti-PTSD effect, a dissociative-promoting effect, an immunostimulatory effect, an anti-cancer effect, an anti-emetic effect, an appetite-stimulating effect, an anti-ulcer effect, an antihistamine effect, an antihypertensive effect, an anti-spasmodic effect, an anti-epileptic effect, a bronchodilator effect, a neuroprotective effect, a nootropic effect, an empathogenic effect, a psychedelic effect, a sedative effect, or a stimulant effect.

29. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 for use in the treatment of a medical condition.

30. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of a medical condition.

31. A method of modulating neurotransmission in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

32. A method of treating a medical condition of a mammal in need of such treatment, the method comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

33. The method according to claim 32, wherein the medical condition is a disorder associated with dysregulation or insufficient function of neurotransmission.

34. The method according to claim 33, wherein the disorder associated with dysregulation or insufficient function of neurotransmission is a disorder of monoaminergic neurotransmission.

35. The method according to claim 34, wherein the disorder associated with dysregulation or insufficient function of neurotransmission is a disorder of serotonergic neurotransmission.

36. The method according to claim 32, wherein the medical condition is a mental health disorder.

37. The mental health disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, substance-induced psychotic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, post-traumatic stress disorder (PTSD), adjustment disorder, mood disorder, depression, atypical depression, postpartum depression, melancholic depression, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, mood swings, anxiety disorder, phobic disorder, eating disorder, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance use disorder, substance-induced mood disorder, mood disorder related to another health condition, disruptive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, and dissociative disorder. The method according to claim 36.

38. The method according to claim 32, wherein the medical condition is a seizure disorder.

39. The method according to claim 28, wherein the seizure disorder is epilepsy.

40. The method according to claim 32, wherein the medical condition is a disorder associated with dysregulation or insufficient function of voltage-dependent ion channels.

41. The method according to claim 40, wherein the voltage-dependent ion channel is a voltage-dependent sodium channel.

42. The method according to claim 41, wherein the compound inhibits the activity of the voltage-dependent sodium channel.

43. The method according to any one of claims 31 to 42, wherein the mammal comprises a genetic variation related to drug metabolism, which is a genetic variation related to the CYP2D6 or CYP3A4 enzyme, or is related to a mental health disorder, a psychological trauma or a stress-related disorder, depression, or an anxiety disorder, and comprises a genetic variation of mGluR5 or FKBP5, or has a genetic variation related to a membrane transporter such as SERT, DAT, NET or VMAT.

44. The method according to any one of claims 31 to 43, wherein the mammal has an altered epigenetic control of a gene whose expression is related to a mental health state or susceptibility to mental health treatment, such as the SIGMAR1 gene for the non-opioid sigma-1 receptor.

45. The method according to any one of claims 31 to 44, wherein the mammal is a human.

46. A method for reducing symptoms of a mental health disorder in a human, comprising identifying a human in need of such reduction, and administering to the human a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

47. A method for reducing symptoms of a mental health disorder in a human, comprising identifying a human in need of such reduction, and administering to the human a pharmaceutical composition according to claim 20.

48. A method for reducing symptoms of a mental health disorder in a human, comprising identifying a human in need of such reduction, and administering to the human a pharmaceutical composition according to any one of claims 21 to 28.

49. A method for improving mental health or function in a human, comprising identifying a human in need of such improvement, and administering to the human a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

50. A method for improving mental health or function in a human, comprising identifying a human in need of such improvement, and administering to the human a pharmaceutical composition according to claim 20.

51. A method for improving mental health or function in a human, comprising identifying a human in need of such improvement, and administering to the human a pharmaceutical composition according to any one of claims 21 to 28.

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