Methods of using n-substituted indole neuroplastogens

Abstract

The present invention relates to methods of treating diseases or disorders that are mediated by the loss of synaptic connectivity and / or plasticity, such as neurological diseases and disorders including obsessive compulsive disorder (OCD), Alzheimer's disease psychosis or psychosis in Alzheimer's disease (AD-P), frontotemporal dementia (FID), behavioral and psychological symptoms in dementia, motor symptoms in Parkinson's disease, and behavioral and psychological symptoms in Parkinson's disease, with (R)-1- (5-methoxy-1H-indol-1-y1)-N,N-dimethylpropan-2-amine (zalsupindole; AAZ-A-154). or a pharmaceutically acceptable salt or solvate thereof.

Description

WSGR Docket No. 55776-732.601METHODS OF USING N-SUBSTITUTED INDOLE NEUROPLASTOGENSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 699,016, filed on September 25, 2024, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] Described herein are compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for the treatment of conditions, diseases, or disorders that would benefitfrompromotingneuronal growth and / or improvingneuronal structure.BACKGROUND OF THE INVENTION

[0003] Altered synaptic connectivity and plasticity has been observed in the brains of individuals with neurological diseases and disorders. Psychoplastogens promote neuronal growth and improve neuronal architecture through mechanisms involving the activation of AMPA receptors, the tropomyosin receptor kinaseB (TrkB), and the mammalian target of rapamycin (mTOR). Modulators of these biological targets, such as, for example, ketamine, scopolamine, N,N-dimethyltryptamine (DMT), and rapastinel have demonstrated psychoplastogenic properties. For example, ketamine is capable of rectifying deleterious changes in neuronal structure that are associated with neurological diseases and disorders. Such structural alterations include, for example, the loss of dendritic spines and synapses in the prefrontal cortex (PFC) as well as reductions in dendritic arbor complexity. Furthermore, pyramidal neurons in the PFC exhibit top-down control over areas of the brain controlling motivation, fear, and reward. Psychedelic psychoplastogens have demonstrated antidepressant, anxiolytic, and anti -addictive effects of in the clinic.BRIEF SUMMARY OF THE INVENTION

[0004] In one aspect, provided herein is a method of treating a brain disorder selected from obsessive compulsive disorder (OCD), Alzheimer’s disease psychosis or psychosis in Alzheimer’s disease (AD-P), frontotemporal dementia (FTD), behavioral and psychological symptoms in dementia, motor symptoms in Parkinson’s disease, and behavioral and psychological symptoms in Parkinson’s disease, comprising administering a therapeutically effective amount of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof.

[0005] Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, thatWSGR Docket No. 55776-732.601 the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.DETAILED DESCRIPTION OF THE INVENTION

[0006] The present disclosure provides non-hallucinogenic (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof as a useful for the treatment of a variety of neurological diseases and disorders as well as increasing neuronal plasticity.

[0007] Psychedelic compounds promote structural and functional neural plasticity in key circuits, elicit therapeutic responses in multiple neuropsychiatric disorders, and produce beneficial neurological effects that can last for months following a single administration. Compounds capable of modifying neural circuits that control motivation, anxiety, and drug-seeking behavior have potential for treating neurological diseases and disorders that are mediated by the loss of synaptic connectivity and / or plasticity . Moreover, such compounds are likely to produce sustained therapeutic effects because, for example, of the potential to treatthe underlying pathological changes in circuitry.Certain Terminology

[0008] Unless otherwise stated, the following terms used in this application have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0009] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0010] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.WSGR Docket No. 55776-732.601

[0011] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0012] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0013] The term “subject” or “patient” encompasses mammals. Examples ofmammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

[0014] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0015] The term “pharmaceutically acceptable,” as used herein, generally refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0016] The term “pharmaceutically acceptable salt,” as used herein, generally refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agentin combination with a suitable cation. Handbookof Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley -VCHWSGR Docket No. 55776-732.6012002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1 -19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non -ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted. Provided herein are non-hallucinogenic compounds that promote neuronal growth and / or improve neuronal structure.Neuroplasticity in Brain Disorders

[0017] Neuronal plasticity, and changes thereof, has been attributed to many brain disorders. For example, during development and in adulthood, changes in dendritic spine number and morphology (e.g., lengths, crossings, density) accompany synapse formation, maintenanceand elimination. These changes are thought to establish and remodel connectivity within neuronal circuits. Furthermore, dendritic spine structural plasticity is coordinated with synaptic function and plasticity. For example, spine enlargement is coordinated with long-term potentiation in neuronal circuits, whereas long-term depression is associated with spine shrinkage.

[0018] In addition, dendritic spines undergo experience-dependent morphological changes in live animals, and even subtle changes in dendritic spines can affect synaptic function, synaptic plasticity, and patterns of connectivity in neuronal circuits. For example, disease-specific disruptions in dendritic spine shape, size, and / or number accompany neurological diseases and disorders, such as, for example, neurodegenerative (e.g., Alzheimer’s disease or Parkinson’s disease) and neuropsychiatric (e.g., depression or schizophrenia) diseases and disorders, suggesting that dendritic spines may serve as a common substrate in diseases that involve deficits in information processing.

[0019] In some embodiments, (R)-l-(5 -methoxy- lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, enhances neuroplasticity and improves dendritic spine number and dendritic spine morphology that is lost in brain disorders.

[0020] In some embodiments, the experiment or assay to determine increased neuronal plasticity of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2Abinding assay, or a 5-HT2Ablocking experiment (e.g., ketanserin blocking experiments).WSGR Docket No. 55776-732.601Compounds

[0021] Provided herein is (R)-l -(5 -methoxy- lH-indol-l-yl)-N,N-dimethylpropan-2 -amine, or a pharmaceutically acceptable salt or solvate thereof. (R)- 1 -(5 -meth oxy-1 H-indol-l-yl)-N,N- dimethylpropan-2-amine has the structureFurther Forms of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine

[0022] In one embodiment, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine described herein is in the form of a pharmaceutically acceptable salt. In some embodiments, (R)-l- (5 -meth oxy- lH-indol-l-yl)-N,N-dimethylpropan-2-amine is a pharmaceutically acceptable salt, such as, for example, any salt described herein (such as, e.g., a fumarate salt or maleate salt). In some embodiments, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine is a fumarate salt. In some embodiments, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine is a maleate salt.

[0023] Active metabolites of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine having the same type of activity are included in the scope of the present disclosure. In addition, the (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2 -amine described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan- 2-amine are also considered to be disclosed herein.

[0024] In some embodiments, pharmaceutically acceptable salts are obtained by reacting (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine with an acid. In some embodiments, the (R)- l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amineis basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1 -hydroxy-2 -naphthoic acid; 2,2 -dichloroacetic acid; 2- hydroxy ethane sulfonic acid; 2-oxoglutaric acid; 4 -acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzene sulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-l,2-disulfonicacid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;WSGR Docket No. 55776-732.601 lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene- 1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid ( ); and undecylenic acid.

[0025] In some embodiments (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine is basic and is reacted with maleic acid.

[0026] In some embodiments (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine is basic and is reacted with fumaric acid.

[0027] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine are conveniently prepared orformed during the processes described herein and known in the art. In addition, (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2 -amine may exist in unsolvated as well as solvated forms.

[0028] The methods and formulations described herein include the use of 7V-oxides, pharmaceutically acceptable salts, isotopically enriched derivatives, as well as active metabolites of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine having the same type of activity.

[0029] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of (R)- 1 -(5 -methoxy- 1 H-indol- 1 -yl)-N,N-dimethylpropan-2 -amine are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituentto decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, deuterium or a deuteroalkyl group.

[0030] In another embodiment, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amineis labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0031] Described herein are isotopically-labeled derivatives of (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into (R)- 1 -(5 -meth oxy-1 H-indol- l-yl)-N,N-WSGR Docket No. 55776-732.601 dimethylpropan-2-amine include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36C1,, 23L i24j;i3i J, 32pan(j 33p jn oneembodiment, (R)- 1 -(5 -meth oxy-1 H-indol-l-y 1)-N,N- dimethylpropan-2-amine isotopically -labeled with3H and14C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens of the (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine are replaced with deuterium.Pharmaceutical compositions

[0032] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amountof (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2 -amine, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0033] In some embodiments, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine is formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975 ; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. , 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[0034] In some emb odiments, the (R)- 1 -(5 -methoxy- 1 H-indol- 1 -yl)-N,N-dimethy lpropan-2-amine is administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the (R)-l-(5-methoxy-lH-indol-l- yl)-N,N-dimethylpropan-2-amine and compositions described herein can be affected by any method that enables delivery of the compound to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal,WSGR Docket No. 55776-732.601 intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon the condition and disorder of the recipient.

[0035] By way of example only, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

[0036] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amountof (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non -aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, (R)-l -(5-methoxy-lH-indol-l -yl)- N,N-dimethylpropan-2 -amine is presented as a bolus, electuary or paste.

[0037] Pharmaceutical compositions which can be used orally include tablets, push -fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain (R)-l-(5-methoxy-lH- indol-l-yl)-N,N-dimethylpropan-2 -amine in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of (R)-l -(5-methoxy- lH-indol-l-yl)-N,N-dimethylpropan-2-amine doses.WSGR Docket No. 55776-732.601

[0038] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen -free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0039] Pharmaceutical compositions for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan- 2-amine which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions whichmay include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine to allow for the preparation of highly concentrated solutions.

[0040] It should be understood that in addition to the ingredients particularly mentioned above, the (R)- 1 -(5 -methoxy- 1 H-indol- 1 -yl)-N,N-dimethylpropan-2 -amine and compositions describ ed herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.Methods of Treatment

[0041] In one aspect, provided herein is a method of treating a brain disorder selected from obsessive compulsive disorder (OCD), Alzheimer’s disease psychosis or psychosis in Alzheimer’s disease (AD-P), frontotemporal dementia (FTD), behavioral and psychological symptoms in dementia, motor symptoms in Parkinson’s disease, and behavioral and psychological symptoms in Parkinson’s disease, comprising administering a therapeutically effective amount of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof.WSGR Docket No. 55776-732.601

[0042] Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0043] In certain embodiments, the compositions containingthe (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a mammal already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the mammal’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0044] In prophylactic applications, compositions containing (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, are administered to a mammal susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the mammal’s state of health, weight, and the like. When used in mammals, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal’s health status and response to the drugs, and the judgment of a healthcare professional. In one embodiment, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising (R)-l-(5-methoxy- lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, in order to prevent a return of the symptoms of the disease or condition.

[0045] In certain embodiments wherein the mammal’s condition does not improve, upon the discretion of a healthcare professional the administration (R)- 1 -(5 -meth oxy-1 H-indol-l-y 1)-N,N- dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, is administered chronically, that is, for an extended period of time, including throughout the duration of the mammal’s life in order to ameliorate or otherwise control or limit the symptoms of the mammal’s disease or condition.

[0046] In certain embodiments wherein a mammal’s status does improve, the dose of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine administered is temporarily reduced orWSGR Docket No. 55776-732.601 temporarily suspendedfor a certain length of time (ie., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, includingby way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0047] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the mammal requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0048] The amount of a given agent administered to a subject depends upon factors such as the disease condition and its severity, the identity (e.g., weight, sex) of the subject in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the route of administration, the condition being treated, and the subject or host being treated.

[0049] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one embodiment, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub -doses per day.

[0050] In one embodiment, the daily dosages appropriate for (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0051] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and itis expressed as the ratio between LD50and ED50. In certain embodiments,WSGR Docket No. 55776-732.601 the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof lies within a range of circulating concentrations that include the ED50with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0052] In any of the aforementioned aspects are further embodiments in which the effective amount of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal.

[0053] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan- 2-amine, or a pharmaceutically acceptable salt or solvate thereof, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[0054] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan- 2-amine, or a pharmaceutically acceptable salt or solvate thereof, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0055] In one embodiment, the therapeutic effectiveness of (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, is enhanced by administration of an adjuvant (ie., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased byWSGR Docket No. 55776-732.601 administering (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0056] In certain embodiments, different therapeutically-effective dosages of (R)-l-(5-methoxy- lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, will be utilized in formulating a pharmaceutical composition and / or in treatment regimens. (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2 -amine may be administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention / treatment described herein encompasses the use of metronomic dosing, i.e., providingmore frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of (R)- 1 -(5 -meth oxy-1 H-indol-l-y 1)-N,N- dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time duringtreatmentwith the second agent or after termination of treatment with the second agent. It also includes treatments in which (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0057] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some embodiments, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.EXAMPLES

[0058] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.I. CHEMICAL SYNTHESIS

[0059] (R)-l -(5 -methoxy- 1 H-indol-l-y l)-N,N-dimethylpropan-2-amine is synthesized as described previously, for example, in WO2023114313 Al filed December 14, 2022, which is herein incorporated by reference for such disclosure.WSGR Docket No. 55776-732.601II. PHARMACEUTICAL COMPOSITIONSExample A-l: Parenteral Pharmaceutical Composition

[0060] To prepare a parenteral pharmaceutical composition suitable for administrationby injection (subcutaneous, intravenous), 1 -1000 mg of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan- 2-amine, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer is optionally added as well as optional acid or base to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection.Example A-2: Oral Solution

[0061] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s), optional buffer(s) and taste masking excipients) to provide a 20 mg / mL solution.Example A-3: Oral Tablet

[0062] A tablet is prepared by mixing 20-50% by weight of (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.Example A-4: Oral Capsule

[0063] To prepare a pharmaceutical composition for oral delivery, 1 -1000 mg of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0064] In another embodiment, 1-1000 mg of (R)- 1 -(5 -methoxy- IH-indol-l -yl)-N,N- dimethylpropan-2-amine, or a pharmaceutically acceptable salt thereof, is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.III. BIOLOGICAL EXAMPLES

[0065] In some embodiments, the plastogenic potential of (R)- 1 -(5 -methoxy- IH-indol-l -yl)-N,N- dimethylpropan-2-amine is assessed by measuring the changes in neurite development.Example B-l:

[0066] Dendritogenesis Assays. Phenotypic screening has historically proven more successful than target-based approaches for identifying drugs with novel mechanisms of action. Using a phenotypic assay, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2 -amine is tested fortheirWSGR Docket No. 55776-732.601 ability to increase dendritic arbor complexity in cultures of cortical neurons. Following treatment, neurons are fixed and visualized using an antibody against MAP2 — a cytoskeletal protein localized to the somatodendritic compartment of neurons. Sholl analysis is then performed, and the maximum number of crossings (Nmax) is used as a quantitative metric of dendritic arbor complexity. For statistical comparisons between specific compounds, the raw Nmaxvalues are compared. Percent efficacies are determined by setting the Nmaxvalues for the vehicle (DMSO) and positive (ketamine) controls equal to 0% and 100%, respectively.

[0067] Animals. For the dendritogenesis experiments, timed pregnant Sprague Dawley rats are obtained from Charles River Laboratories (Wilmington, MA). In some instances, male and female C57BL / 6J mice are obtained from Jackson Lab oratory (Sacramento, C.A.). In some instances, mice are housed in a temperature and humidity -controlled room maintained on a 12-h light / dark cycle in groups of 4-5 (same sex).Example B-2:

[0068] Dendritogenesis - Sholl Analysis. Neurons are plated in 96-well format (200 pL of media per well) at a density of approximately 15,000 cells / well in Neurobasal (Life Technologies) containing 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine serum, and 0.5 mM glutamine. After 24 h, the medium is replaced with Neurobasal containing lx B27 supplement (Life Technologies), 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 pM glutamate. After 3 days in vitro (DIV3), the cells are treated with compounds (e.g., (R)- 1 -(5 -meth oxy-1 H-indol-l-y 1)-N,N- dimethylpropan-2-amine). Compounds tested in the dendritogenesis assays are treated at 10 pM unless noted otherwise. Stock solutions of the compounds in DMSO are first diluted 100 -fold in Neurobasal before an additional 10-fold dilution into each well (total dilution = 1 :1000; 0.1 % DMSO concentration). Treatments are randomized. After 1 h, the media is removed and replaced with new Neurobasal media containing lx B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 pM glutamate. The cells grow for an additional 71 h. At that time, neurons are fixed by removing 80% of the media and replacing it with a volume of 4% aqueous paraformaldehyde (Alfa Aesar) equal to 50% of the working volume of the well. Then, the cells are incubated at room temperature for 20 min before the fixative is aspirated and each well washed twice with DPBS. Cells are permeabilized using 0.2% Triton X-100 (ThermoFisher) in DPBS for 20 minutes at room temperature without shaking. Plates are blocked with antibody diluting buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS for 1 h at room temperature. Then, plates are incubated overnight at 4°C with gentle shaking in ADB containing a chicken anti-MAP2 antibody (1 : 10,000; EnCor, CPCA-MAP2). The next day, plates are washed three times with DPBS and once with 2% ADB in DPBS. Plates are incubated for 1 h at room temperature in ADB containing an anti -chickenWSGR Docket No. 55776-732.601IgG secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, 1 :500) and washed five times with DPBS. After the final wash, 100 pL of DPBS is added per well and imaged on an ImageXpress Micro XL High-Content Screening System (Molecular Devices, Sunnyvale, CA) with a 2 Ox objective.

[0069] Images are analyzedusinglmageJFiji (version 1.51W). First, images correspondingto each treatment are sorted into individual f olders that are then blinded f or data analysis. Plate controls (both positive and negative) are used to ensure that the assay is working properly as well as to visually determine appropriate numerical values for brightness / contrast and thresholding to be applied universally to the remainder of the randomized images. Next, the brightness / contrast settings are applied, and approximately 1-2 individual pyramidal-like neurons per image (i.e., no bipolar neurons) are selected using the rectangular selection tool and saved as separate files. Neurons are selected that did not overlap extensively with other cells or extend far beyond the field of view. The threshold settings are then applied to the individual images. The paintbrush tool is used to eliminate artifacts and dendritic processes originating from adjacent neurons (cleanup phaseNext, the pointtool is used to select the center of the neuron, and the images are saved and processed using the following Sholl analysis batch macro: run("Sholl Analysis...", "starting=O ending=NaN radius_step=2 #_samples=l integration=Mean enclosing= l #_primary=4 infer fit linear polynomial=[Best fitting degree] most semi-log normalizer=Area create background=228 save do");Sholl analysis circle radii = 2 pixel increments = 0.67 pm. All images are taken and analyzed by an experimenter blinded to treatment conditions. The number of crossings for each neuron at each distinct radius is averaged to produce an average Sholl plot for each treatment. The Nmaxvalues are simply determined by identifying the maximum of each plot. For each treatment, neurons are selected from at least 6 wells spread across 2 plates (9 sites / well x 3 wells / plate x 2 plates). Each plate is prepared using neurons obtained from independent pregnant dams).Example B-3:

[0070] Spinogenesis Experiments. Spinogenesis experiments are performed as previously describ ed with the exception that cells are treated on DIV 19 and fixed 24 h after treatment on DIV20. (Ly, C. et al., 2018) The images are taken on a Nikon HCA Confocal microscope a with a lOOx / NA 1.45 oil objective. DMSO and ketamine (10 pM) are used as vehicle and positive controls, respectively. (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine was found to significantly increase PFC layer V pyramidal neuron spine density (number of spines / pm length) compared to vehicle control at 10 mg / kg and 30 mg / kg.WSGR Docket No. 55776-732.601Example B-4:

[0071] Neurite Outgrowth Assay. Changes in the pattern of neurite outgrowth have been implicated in psychiatric and neuro degenerative disorders as well as traumatic injuries. The discovery of new compounds that can positively affect neuritogenesis are important for developing new therapeutics for neurological diseases. Measurement of neurite outgrowth of rat cortical neurons using an automated image-based assay was used to determine the neuroplastic effects of the compounds of the present invention. The neurite outgrowth assay was performed atNeurofit SAS (France) as described below.

[0072] Pregnant Wistar rats (Janvier; France) were used for the study. They were delivered 6 days before their use. Upon arrival at Neurofit animal facility, they were housed one per cage and maintained in a room with controlled temperature (21 -22°C) and a reversed light-dark cycle (12h / 12h; lights on: 17:30 -05:30; lightsoff: 05 :30- 17:30)withfoodandwateravailable ad libitum.

[0073] Female Wistar rats of 17 days gestation were killed by cervical dislocation and the fetuses were removed from the uterus. Their brains were placed in ice-cold medium of Leibovitz (LI 5, Gibco, Fisher bioblock, France). Cortices were dissected and meninges were carefully removed. The cortical neurons were dissociated by trypsinization for 30 min at 37°C (trypsin-EDTA, Gibco) in presence of 0.1 mg / ml DNAse I (Roche, France). The reaction was stoppedby addition of Dulbecco’s Modified Eagle Medium (DMEM; Gibco) with 10% of fetal bovine serum (FBS; Gibco). The suspension was triturated with a 10-ml pipette and using a needle syringe 21 G and centrifuged at 350 x g for 10 min at room temperature. The pellet of dissociated cells was resuspended in a medium consisting of Neurobasal (Gibco) supplemented with 2% B27 supplement (Gibco), 0.5mM L- Glutamine (Gibco), an antibiotic-antimicotic mixture. Viable cells were counted in a Neubauer cytometer using the trypan blue exclusion test (Sigma). Cells were seeded at a density of 10000 cells per well in 96-well plate (Costar) precoated with poly -L-lysine. (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine at different concentrations was added to the cultures. Donepezil (positive control) was tested at 250 nM.

[0074] After 72h (3 days) of plating, cultures were fixed with paraformaldehyde in PBS (4%, Sigma) for 30 min at 4°C. Then, cells were successively permeabilized with 0.1% Triton X100 for 30 min, saturated with PBS containing 3% of BSA and were incubated Ih with anti -beta III tubulin antibody (Sigma) at 1 / 10 000 in PBS containing 0.5% of BSA. Cells were washed three times with PBS containing 0.5% of BSA, and they were incubated Ih with goat anti -mouse antibody coupled with AF488 (Invitrogen Al 1001) diluted at l / 1000 in PBS containing 0.5% of BSA. Finally, nuclei were staining with DAPI 1 mg / ml at l / 1000 inPBS containing 0.5% ofBSA. Afterrinsingwith PBS, the plate was filmed and neurite networks were examined and analyzed using High -ContentWSGR Docket No. 55776-732.601Screening (Celllnsight, Thermo Scientific). The average number of neurites per neuron and the average total length of neurites per neuron were the main parameters analyzed. Analysis of data was performed using analysis of variance(ANOVA). The Fisher’s Protected Least SignificantDifference test was used for multiple comparisons. A p value < 0.05 was considered significant. The software used is StatView 5.0 from SAS Institut.

[0075] In some embodiments, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine increases the pattern of neurite outgrowth. In some embodiments, (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine increases neurite average length compared to a control. In some embodiments, (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine increases neurite branch points compared to a control. In some embodiments, (R)- 1 -(5 -meth oxy-1 H-indol-l-y 1)-N,N- dimethylpropan-2-amine significantly increases the number of new neurites and / or the average neurite length compared to a control.

[0076] (R)- 1 -(5 -methoxy- 1 H-indol-l-y l)-N,N-dimethylpropan-2-amine was found to significantly increase average total neurite length per neuron at doses of 0.3 pM, I pM, 3 pM, lOpM, and 30pM compared to control.Example B-5:

[0077] Spontaneous EPSC Experiments. Spontaneous EPSC frequency, a measure of synaptic connectivity, was determinedin PFC layer V pyramidal neurons. (R)-l-(5-methoxy-lH-indol-l-yl)- N,N-dimethylpropan-2-amine (lOmg / kg, ip) significantly increased the EPSC frequency (Hz) compared to vehicle control. Spontaneous EPSC amplitude, a measure of synaptic strength, was determined in PFC layer V pyramidal neurons. (R)- 1 -(5 -meth oxy-1 H-indol-l-y 1)-N,N- dimethylpropan-2-amine (lOmg / kg, ip) significantly increased the EPSC amplitude (pA) compared to vehicle control.Example B-6:

[0078] Forced Swim Test. As increased cortical structural plasticity in the anterior parts of the brain mediates the sustained (>24 h) antidepressant-like effects of ketamine and play a role in the therapeutic effects of 5 -HT2 A agonists, the impact of compoundson forced swim test (FST) behavior can be used evaluate therapeutic potential of the compound provided herein. For example, first, a pretest would be used to induce a depressive phenotype. Test compound could then be administered 24 h after the pre-test, and the FST performed 24 h and 7 d post drug administration.

[0079] A sample protocol of a forced swim test is included below:

[0080] Male Sprague Dawley rats are obtained and housed 3 rats per cage following an IACUC approved protocol. All experiments are carried out at ambient temperatures (20 and 23°C) under artificial lighting during the light-on part of the light / dark cycle in a Forced Swim chamberWSGR Docket No. 55776-732.601 constructed of clear acrylic (height = 40 cm; diameter = 20.3 cm). Only one rat is placedin the swim chamber at a time for each swim test. The water is changed and the chamber cleaned between each animal. All rats are exposed to two swim sessions. The water depth is 16 cm in the first swim session and 30 cm in the second swim session, and the water temperature is maintained at23±l °C for all swim sessions. During the FST, animals undergo a 15 min swim session (pre-swim), lasting for 15 minutes, dried with paper towels, and returned to the home cage. Rats are injected with either saline, ketamine (positive control), or test compound after the habituation session, returned to home cage, and then tested in a second FST lasting 5 minutes ~24 hours (second swim test) later. The second swim test is video recorded for scoring. Body weights are measured on both days. Scoring of the second swim test is performed by trained technicians using a time sampling technique in which the animal in the video recorded test is viewed every 5 seconds and the behavior seen is noted. The measures noted are immobility, climbing, and swimming behaviors.Example B-7:

[0081] Head Twitch Response to Assess Hallucinogenic Potential of Compound. Hallucinogenic compound 5-MeO-DMT produces a robust, dose-dependent head-twitch response (HTR) in mice. However, the isosteric compound 6-MeO-DMT is significantly less potent. As expected based on drug-discrimination data, 6-MeO-DMT does not produce a HTR. Finally, potent plasticity -promoting compounds do not produce a HTR, demonstrating that hallucinogenic potential and neuroplastogenicity can be decoupled.

[0082] The compound provided herein can be assessed for hallucinogenic potential using a head twitch response assay. A sample protocol of a head twitch response assay is included below:

[0083] C57BL / 6JMice (9-10 weeks old) are housed following an IACUC approved protocol. The mice are habituated in the test cage for at least 30 min, injected intraperitoneally with compound (injection volume 5 ml / kg), returned to the empty test cage, and filmed for 20 minutes. Each video is scored for the number of head-twitches by a trained observer blinded to treatment condition.Example B-8:

[0084] Preclinical Parkinson’s disease models. The compound provided herein can be tested in a a-Syn PFF mouse model of Parkinson’s disease. A sample protocol of a preclinical Parkinson’s disease model is included below:

[0085] On day 0, mice are injected with a-Syn PFF in the Substantia Nigra Pars Compacta (SNpc). Mice may also be further treated with conduritol P-epoxide (CBE) to induce additional injury. Test compound is dosed IP on days 18, 19, and 20. Motor function is assessed on a ladder test on days 21 and 28. L-Dopa is administered 2-hours before testing as a positive control.WSGR Docket No. 55776-732.601IV. CLINICAL EXAMPLES

[0086] Efficacy ofthe compound providedherein canbe assessedthough the following clinical study protocols:Example C-l: Efficacy of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine in OCD: a Double-Blind, Placebo-Controlled Study

[0087] Study Aim : The purpose of this study is to investigate effects of (R)-l -(5 -methoxy- IH-indol- l-yl)-N,N-dimethylpropan-2-amine on OCD and its symptoms. OCD symptom severity will be assessed before treatment and 24 and 48 hours after treatment, one week after treatment, two weeks after treatment, one month after treatment, and three months after treatment.

[0088] This study will be a randomized, active-placebo-controlled, double-blind design to examine the clinical and neural effects on OCD, of either (R)- 1 -(5 -meth oxy-1 H-indol-l-y 1)-N,N- dimethylpropan-2-amine or active placebo-control agent (niacin), given along with non -drug preparatory and follow-up support appointments to 30 study participants. The duration of the randomized study phase is from consent until two weeks after drug administration. Participants will be followed for 12 weeks (3 months) post-study drug administration.

[0089] Inclusion Criteria:• Primary DSM-5 diagnosis of OCD• Y-BOCS score of 19 or greater• Failure of at least one trial of standard care treatment (medication and / or psychotherapy [CBT / ERP]) for OCD• Non-consumption of SSRIs for at least 8 weeks at the time of randomization• Willingness to refrain from psychiatric medications (e.g., antidepressants, first- and second- generation antipsychotics, mood stabilizers) during the study period, as well as certain other medications (e.g., anti-seizure medications, cardiovascular medications, and aldomet specifically) during the day of dosing• Willingness to abstain from THC -containing products for study duration. A negative urinary drug screen is also required at baseline and the day of dosing.• A negative urinary pregnancy screen at study entry and day of dosing if of childbearing potential, and willingness to use adequate birth control for study duration

[0090] Exclusion Criteria:• Personal or immediate family history of schizophrenia spectrum and other psychotic disorders, bipolar I or II disorder, or major depressive disorder with psychotic features• Active suicidal intent• Unremitted Tourette syndromeWSGR Docket No. 55776-732.601• Autism spectrum disorder• OCPD or BPD• Current substance use disorder (except mild alcohol use disorder)• Unstable neurological or medical condition(s) that may render study procedures unsafe, including poorly managed diabetes, hypertension, or cardiovascular conditions, or history of seizure(s) or chronic / severe headaches• Any history of head injury with loss of consciousness for more than 30 minutes• Any contraindications to undergoing an MRI scan, including having metal implants or metal fragments in the body• Any use of psychedelic substances within the prior 12 monthsExample C-2: A Study of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine in Adult and Elderly Subjects Experiencing Neuropsychiatric Symptoms Related to Neurodegenerative Disease

[0091] Study Aim: The purpose of this study is to assess the safety and tolerability of (R)-l-(5- methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine compared to placebo in adult and elderly subjects with neuropsychiatric symptoms related to neurodegenerative disease. Such neurodegenerative diseases include, for example, Parkinson's disease with or without dementia, Dementia with Lewy bodies (DLB), All-cause dementia with possible or probable Alzheimefs disease (AD), and / or Frontotemporal degeneration (FTD) spectrum disorders.

[0092] Primary Outcome Measure:• Number (%) of patients with Treatment -Emergent Adverse Events (TEAEs)

[0093] Secondary Outcome Measures:• Change From Baseline to Week 8 in Montreal Cognitive Assessment (MoCA)

[0094] Inclusion Criteria:• Subject requires some or complete assistance with one or more of the following:1 . Instrumental activities of daily living (communication, transportation, meal preparation, shopping, housework, managing medications, managing personal finances) OR2. Basic activities of daily living (personal hygiene, dressing, eating, maintaining continence or transferring)• Meets clinical criteria for at least one of the following disorders, with or without cerebrovascular disease (CVD):1 . Parkinson's disease with or without dementia as defined by the Movement Disorder Society's Task Force2. Dementia with Lewy bodies (DLB)WSGR Docket No. 55776-732.6013. All-cause dementia, possible or probable Alzheimer's disease (AD)4. Frontotemporal degeneration spectrum disorders, including possible or probable: i. Behavioral variant frontotemporal dementia ii. Progressive supranuclear palsy iii. Corticobasal degeneration5. Vascular dementia, including post-stroke dementia multi-infarct dementia and / or subcortical ischemic vascular dementia (SIVD)• If the subject is female, she must not be pregnant or breastfeeding. She must also be of nonchildbearing potential (defined as either surgically sterilized or at least 1 year postmenopausal) or must agree to use a clinically acceptable method of contraception or be abstinent.• If the subject is taking an antipsychotic medication at the time of screening, the antipsychotic medication must be discontinued 2 weeks or 5 half -lives (whichever is longer)

[0095] Exclusion Criteria:• Has psychotic symptoms that are primarily attributable to delirium or substance abuse (i.e., neuropsychiatric symptoms not related to neurodegenerative disease)• Has current evidence of an unstable neurological, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including cancer or malignancies that, in the judgment of the Investigator, would jeopardize the safe participation of the subject in the study or significantly interfere with the conduct or interpretation of the study• Has a known personal or family history of long QT syndrome or family history of sudden cardiac death• Has a clinical significant CNS abnormality that is most likely contributing to the dementia or findings on MRI or CT including: a. intracranial mass lesion b. vascular malformation c. evidence of >4 hemosiderin deposits• The urine drug screen result at Visit 1 (Screening) indicates the presence of amphetamine / methamphetamine, barbiturates, cocaine, or phencyclidine (PCP). Subjects who test positive for amphetamines and who have a valid prescription may be retested if they agree to abstain from the medication for the length of their participation in the study. The presence of benzodiazepines, marijuana (THC), or opiates does not necessarily exclude the subject from the study, as assessed by the Investigator in consultation with the Medical Monitor.WSGR Docket No. 55776-732.601

[0096] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WSGR Docket No. 55776-732.601CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a brain disorder selected from obsessive compulsive disorder (OCD), Alzheimer’s disease psychosis or psychosis in Alzheimer’s disease (AD-P), frontotemporal dementia (FTD), behavioral and psychological symptoms in dementia, motor symptoms in Parkinson’s disease, and behavioral and psychological symptoms in Parkinson’s disease, comprising administering a therapeutically effective amount of (R)-l -(5 -methoxy- IH-indol- l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof.2 A method of treating a brain disorder selected from obsessive compulsive disorder (OCD), Alzheimer’s disease psychosis or psychosis in Alzheimer’s disease (AD-P), frontotemporal dementia (FTD), behavioral and psychological symptoms in dementia, motor symptoms in Parkinson’s disease, and behavioral and psychological symptoms in Parkinson’s disease, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of (R)-l-(5-methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof.3 The method of claim 2, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.

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