How to Treat PTSD and Neurological Disorders

Abstract

The embodiment includes therapeutic small molecules for use in treating addiction and neurological disorders by stimulating neuroplasticity.The therapeutic small molecules can enhance neuroplasticity and improve neuronal function by affecting upstream regulators of FOS, JUN, BDNF, CDC42 and CCL2.The therapeutic small molecules can also help reduce amyloid plaques through binding to amyloid beta (a4).

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 288,365, filed December 10, 2021, the contents of which are incorporated herein by reference.

[0002] Sequence Listing Reference This application contains an electronically submitted Sequence Listing in ASCII format, which is hereby incorporated by reference in its entirety.

[0003] FIELD OF THEINVENTION The present invention relates to small molecules with therapeutic applications, in particular it relates to novel small molecules and methods for treating conditions such as neurological disorders and addictions. [Background technology]

[0004] Addiction can be defined as a biopsychosocial disorder characterized by compulsive engagement in rewarding stimuli despite harmful consequences. Addiction affects more than 19.7 million people in the United States and is the cause of great financial and personal damage. The overall economic costs are greater than those of all types of diabetes and all cancers. These costs arise, for example, from the direct adverse effects of drugs and associated health care costs, long-term complications, lost productivity and associated welfare costs, accidents, suicides, homicides and incarceration. To date, there have been few effective pharmacological interventions, and none have completely resolved the damage to the brain of addiction.

[0005] Substance use disorder (SUD) can be defined as the persistent use of a drug despite significant harmful and untoward consequences. Individuals become increasingly dependent on the drug, so that cessation of use results in withdrawal symptoms such as dysphoria. Substance use disorder is characterized by a variety of mental / emotional, physical, and behavioral disorders such as chronic guilt, inability to reduce or stop consuming the substance despite repeated attempts, drinking while driving, and physiological withdrawal symptoms. The development of dependence is conceptualized as a neurobehavioral disorder that progresses from compulsive drug use to compulsive drug abuse.

[0006] The term "behavioral addiction" can be defined as a compulsive drive to engage in natural rewards, which are intrinsically rewarding (i.e., desirable or attractive) behaviors. Preclinical evidence has demonstrated that a marked increase in ΔFosB expression by repeated and excessive exposure to natural rewards induces the same behavioral effects and neuroplasticity as those that occur in drug addiction.

[0007] The Brain Disease Model of Addiction (BDMA) identifies addiction as a chronic, relapsing brain disease and suggests that effective treatment for addiction involves pharmaceutical and other medical interventions. The BDMA asserts that SUDs are chronic, relapsing brain diseases, and that relapses are a symptom and part of the expected course of the disease. As with other diseases, SUDs may have multiple causes, including behavioral, environmental, and biological influences. Two specific proteins, ΔFosB and BDNF, have been associated with addiction and SUDs.

[0008] The protein fosB, also known as FosB and G0 / G1 switch regulatory protein 3 (G0S3), is a protein encoded in humans by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene. The ΔFosB splice variant has been identified as playing a central and crucial (necessary and sufficient) role in the development and maintenance of addiction. ΔFosB overexpression (i.e., abnormally and excessively high levels of ΔFosB expression that produce a pronounced gene-related phenotype) induces the development of addiction-related neuroplasticity throughout the reward system and produces behavioral phenotypes characteristic of addiction.

[0009] Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF acts on specific neurons in the central and peripheral nervous systems, helping to support the survival of existing neurons and promoting the growth and differentiation of new neurons and synapses.

[0010] Neuroplasticity, also known as neural plasticity or brain plasticity, is the ability to change neural networks in the brain through growth or reorganization. These changes range from individual neuronal pathways making new connections to systematic adjustments such as cortical remapping. Examples of neuroplasticity include changes in circuits and networks due to learning new abilities, environmental influences, practice, and mental stress. Although neuroplasticity was previously thought to only emerge during childhood, recent studies have demonstrated that many aspects of the brain can be further altered (i.e., are "plastic") throughout adulthood. However, the developing brain exhibits a greater degree of plasticity than the adult brain. Activity-dependent plasticity may have important implications for healthy development, learning, memory, and recovery from brain injury.

[0011] Based on recent studies, modulation of gene expression has been proposed as a mechanism of drug addiction. Among other potential genes, induction or inhibition of FosB and / or BDNF has been proposed. However, direct interaction with FosB or BDNF has not yet resulted in significant improvement in the brain dysfunction of addiction. Studies have shown slight improvements with cannabinoid therapy, cranial stimulation and ketamine treatment. However, such improvements have not been widely accepted by the medical community.

[0012] There is a need for pharmaceutical agents to treat addiction, as conventional treatments for addiction are generally ineffective. Such treatments should have therapeutic effects via promoting neuroplasticity. Thus, embodiments of the present invention include therapeutic peptides for treating addiction along with other disorders, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Summary of the Invention

[0013] The invention described and claimed herein has many features and embodiments, including, but not limited to, those shown or described or referenced in this Summary. The invention described and claimed herein is not limited to or by the features or embodiments identified in this Summary, which are included by way of example only and not limitation.

[0014] Based on the novel interpretation of molecular mechanisms obtained from biopsy brain tissue, applicants have identified several underlying mechanisms for remodeling the addicted brain and resolving addiction. Technology has revealed many promising signaling mechanisms in treating illnesses such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). In the embodiments described herein, applicants present specific targeted therapeutic methods for treating such illnesses.

[0015] It is therefore an object of the present invention to provide novel compounds that stimulate neuroplasticity. Another object of the present invention is to provide novel compounds for treating neurological disorders and / or addictions.

[0016] One embodiment is a method of treating neurological disorders and / or addictions by stimulating neuroplasticity with small molecule therapeutics.

[0017] One embodiment is a method of stimulating neuroplasticity using small molecule therapeutics. Another embodiment is a method of preventing neurological disorders and / or addictions by stimulating neuroplasticity using small molecule therapeutics.

[0018] Applicants provide a compound of formula I, or an analog thereof: [ka]

[0019] In another embodiment, the present invention provides a compound, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, and E3: [ka] TIFF2025500034000004.tif216159TIFF2025500034000005.tif212159TIFF2025500034000006.tif124159

[0020] In one embodiment, the compounds described herein are useful in improving neuroplasticity. Another embodiment is a method of stimulating neuroplasticity in a subject, where improving neuroplasticity prevents and / or treats a condition such as a neurological disorder or addiction.

[0021] One embodiment is a method of treating a neurological disorder in a subject comprising administering a therapeutically effective amount of a compound of formula I.

[0022] One embodiment is a method of treating a neurological disorder in a subject comprising administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0023] One embodiment is a method for treating, delaying or slowing the progression of, or reducing the rate of cognitive decline in a subject having or at risk of cognitive impairment or decline in cognitive function, the method comprising administering a therapeutic amount of a compound disclosed herein.

[0024] One embodiment is a method of treating a condition by administering a therapeutic amount of a compound of formula I. The condition can be, for example, anxiety, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, epilepsy and seizures, Guillain-Barre syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headache, encephalitis, and myasthenia gravis.

[0025] One embodiment is a method of treating a condition by administering a therapeutic amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, and E3. The condition can be, for example, inflammation, poisoning, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, epilepsy and seizures, Guillain-Barre syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headache, encephalitis, and myasthenia gravis.

[0026] One embodiment is a method of treating addiction in a subject comprising administering a therapeutically effective amount of a compound of formula I.

[0027] One embodiment is a method of treating an addiction in a subject comprising administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, and E3. The addiction can be, for example, an addiction to nicotine, cocaine, opioid agonists, or a dependency on stimulants, nicotine, morphine, heroin, other opiates, amphetamines, cocaine, and / or alcohol.

[0028] One embodiment is a method of treating a neurological disorder comprising: (a) identifying a patient having a neurological disorder; and (b) administering a therapeutic molecule to promote neuroplasticity. The therapeutic molecule can be a compound of formula I or an analog of formula I.

[0029] One embodiment is a method of treating a neurological disorder comprising: (a) identifying a patient having a neurological disorder; and (b) administering a therapeutic molecule to promote neuroplasticity. The therapeutic molecule can be selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, and E3.

[0030] One embodiment is a method of treating addiction comprising: (a) identifying a patient with addiction; and (b) administering a therapeutic molecule to promote neuroplasticity. The therapeutic molecule can be a compound of Formula I or an analog of Formula I.

[0031] One embodiment is a method of treating addiction comprising: (a) identifying a patient with addiction; and (b) administering a therapeutic molecule to promote neuroplasticity. The therapeutic molecule can be selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, and E3.

[0032] One embodiment is a method of reversing the potent inhibition of dendritic branching through rebalancing the expression ratio of FOSB, CDC42 and ENTPD4 by administering a therapeutically effective amount of a compound of formula I.

[0033] One embodiment is a method of reversing the potent inhibition of dendritic branching via rebalancing the expression ratios of FOSB, CDC42 and ENTPD4 by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0034] One embodiment is a method of ameliorating disorders of thiamine metabolism by administering a therapeutically effective amount of a compound of formula I.

[0035] One embodiment is a method of ameliorating disorders of thiamine metabolism by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0036] One embodiment is a method of increasing the presence of thiamine metabolism in the brain by administering a therapeutically effective amount of a compound of formula I.

[0037] One embodiment is a method of increasing the presence of thiamine metabolism in the brain by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0038] One embodiment is a method of improving neurometabolism by administering a therapeutically effective amount of a compound of formula I.

[0039] One embodiment is a method of improving neurometabolism by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0040] One embodiment is a method of restoring neuronal excitation thresholds by administering a therapeutically effective amount of a compound of formula I.

[0041] One embodiment is a method of restoring a neural excitation threshold by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0042] One embodiment is a method of reducing the relative abundance of CCL2 by administering a therapeutically effective amount of a compound of formula I.

[0043] One embodiment is a method of reducing the relative abundance of CCL2 by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0044] One embodiment is a method of reducing inflammation through the reduction of CCL2 by administering a therapeutically effective amount of a compound of formula I.

[0045] One embodiment is a method of reducing inflammation through reduction of CCL2 by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0046] One embodiment is a method of improving neurological function by administering a therapeutically effective amount of a compound of formula I.

[0047] One embodiment is a method of improving neurological function by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0048] One embodiment is a method of reducing amyloid plaques through binding to amyloid beta(a4) by administering a therapeutically effective amount of a compound of formula I or an analog of formula I. Accordingly, another embodiment is a method of treating Parkinson's disease by administering a therapeutically effective amount of a compound of formula I or an analog of formula I.

[0049] One embodiment is a method of reducing amyloid plaques through binding to amyloid beta (a4) by administering a therapeutically effective amount of a compound of formula I or an analog of formula I. Accordingly, another embodiment is a method of treating Parkinson's disease by administering a therapeutically effective amount of a compound selected from A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3.

[0050] In one embodiment, the effective amount of a therapeutic compound disclosed herein is about 4 milligrams (mg). In one embodiment, the upper safety limit is about 1.2 grams. In one embodiment, the dose range for clinical administration is about 4 mg to 80 mg.

[0051] In yet another aspect, the present specification provides the use of a therapeutic small molecule or a pharmaceutical composition comprising the same in the preparation of a medicament for the prevention or treatment of a neurological disorder or addiction.

[0052] Other features and advantages of aspects of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention. The accompanying drawings illustrate aspects of the present invention. [Brief description of the drawings]

[0053] [Figure 1] 1 shows the chemical structure of the compound of Formula I ("Somahol") with the atoms numbered. [Diagram 2] 1 shows the oxytocin signaling pathway. [Diagram 3] 1 shows molecular signaling pathways regulated by the 5-HT7 receptor. [Figure 4] RNase I interacting with adjacent genes is shown. [Diagram 5] CCL2 interacting with neighboring genes is shown. [Figure 6] FOSB interacting with neighboring genes is shown. [Figure 7] SLC39A8 interacting with neighboring genes is shown. [Figure 8] C9ORF135 interacting with neighboring genes is shown. [Figure 9] Shows ENTPD4 interacting with neighboring genes. [Figure 10] 1 shows a scaffold molecule, in some embodiments, the hydroxyl and / or carbonyl groups can be replaced with alternative functional groups. [Figure 11] 1 is a graph of the results of a 5-HT2A human serotonin GPCR cell-based agonist restin assay. [Figure 12] 1 is a graph of the results of a 5-HT6 human serotonin GPCR cell-based agonist restin assay. [Figure 13] 1 is a graph of the results of a TrkB human RTK kinase cell-based agonist functional assay. [Figure 14] 1 is a graph of the results of a 5-HT7 human serotonin GPCR cell-based agonist cAMP assay. [Figure 15] 1 is a graph of the results of a 5-HT2B human serotonin GPCR cell-based agonist calcium flux assay. [Figure 16] Table of agonist assay results from each molecule: A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] definition Reference herein to "one embodiment / aspect" or "an embodiment / aspect" means that a particular feature, structure, or characteristic described with respect to that embodiment / aspect is included in at least one embodiment / aspect of the present disclosure. Use of the phrase "in one embodiment / aspect" or "in an embodiment / aspect" in various places herein does not necessarily all refer to the same embodiment / aspect, nor does it refer to mutually exclusive alternative or alternative embodiments / aspects of other embodiments / aspects. Furthermore, various features are described that may be exhibited by some embodiments / aspects and not exhibited by others. Similarly, various requirements are described that may be requirements for some embodiments / aspects and not for other embodiments / aspects. Embodiment and aspect may be used interchangeably in certain instances.

[0055] The terms used herein generally have their ordinary meaning in the art, within the context of this disclosure, and in the specific context in which each term is used.Specific terms used to describe this disclosure are discussed below or elsewhere in this specification to provide additional guidance to practitioners regarding the description of this disclosure.It will be understood that the same thing can be stated in more than one way.

[0056] Thus, alternative terms and synonyms may be used for any one or more terms discussed herein. There is no special significance to whether a term is recited or discussed herein. Synonyms for certain terms are provided. The description of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any term discussed herein, is for illustrative purposes only and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Similarly, this disclosure is not limited to the various embodiments presented herein.

[0057] Without intending to further limit the scope of the present disclosure, the instruments, apparatus, methods and their related results according to the embodiments of the present disclosure are given below. Please note that headings or subheadings may be used in the examples for the convenience of the reader, but do not limit the scope of the present disclosure. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. In case of conflict, this document, including definitions, will control.

[0058] Where applicable, the terms "about" or "generally" as used herein and in the appended claims, and unless otherwise indicated, mean a margin of ±20%. Also, where applicable, the term "substantially" as used herein and in the appended claims, means a margin of ±10% unless otherwise indicated. It is to be understood that not all uses of the above terms are numerically quantifiable such that a reference range may be applied.

[0059] The term "active agent" or "active ingredient" refers to a substance, compound, or molecule that is biologically active or that induces a biological or physiological effect on a subject to which it is administered. In other words, an "active agent" or "active ingredient" refers to a component of a composition that is responsible for all or part of the effect of the composition. An active agent may be a primary active agent, or in other words a component of a composition that is responsible for all or part of the effect of the composition. An active agent may be a secondary agent, or in other words a component of a composition that is responsible for additional parts of the composition and / or other effects. A "pharmaceutical composition" may comprise a combination of an active agent, such as a therapeutic peptide, and a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[0060] The term "analog" or "chemical analog" refers to a compound that has a similar structure to another compound (i.e., Somahol), but differs from it with respect to certain components, which may differ in one or more atoms, functional groups, or substructures that are replaced with other atoms, groups, or substructures.

[0061] The term "alkyl" as used herein alone or as part of another group refers to both straight and branched chain saturated hydrocarbons containing 1 to 20 carbons. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the various branched chain isomers thereof.

[0062] The term "alkylene" as used herein alone or as part of another group refers to a divalent radical of an alkyl group as described above containing 1 to 20 carbons. Examples of alkylene groups are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, and the various branched chain isomers thereof.

[0063] The term "alkenyl" as used herein alone or as part of another group includes both straight and branched chain saturated hydrocarbons containing 2 to 20 carbons, preferably 1 to 12 carbons, more preferably 2 to 8 carbons, and 1 to 6 double bonds. Examples of alkenyl groups are vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, and 4,8,12-tetradecatrienyl.

[0064] The term "alkynyl" as used herein alone or as part of another group includes both straight and branched chain saturated hydrocarbons containing 2-10 carbons, preferably 2-12 carbons, and more preferably 2-8 carbons, and 1-6 triple bonds and optionally 1-3 double bonds. Examples of alkynyl groups are 2-propynyl, 3-butynyl, 4-pentynyl, 2-hexynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, and 4-dodecynyl.

[0065] The term "alkanoyl" or "acyl" as used herein alone or as part of another group refers to an alkyl group attached to a carbonyl group. In the context of the present invention, the terms "alkanoyl" and "acyl" have the same meaning. Thus, C n Alkanoyl or acyl groups are C attached to a carbonyl group. n-1 Alkyl groups. Examples of alkanoyl or acyl groups are acetyl, propionyl and butyroyl.

[0066] The term "alkoxy" as used herein alone or as part of another group refers to an alkyl group containing 1 to 20 carbons, preferably 1 to 10 carbons, and more preferably 1 to 8 carbons, linked to an oxygen atom. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexyloxy, isohexyloxy, heptyloxy, 4,4-dimethylpentoxy, octyloxy, 2,2,4-trimethylpentoxy, nonyloxy, decyloxyl, undecyloxy, dodecyloxy, and the various branched chain isomers thereof.

[0067] The term "cycloalkyl" as used herein alone or as part of another group includes saturated cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl, and tricyclic alkyl systems, and a total of 3 to 20 carbon atoms, preferably 3 to 10 carbons, forming part of the ring system. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, adamantyl, and bicyclo[3.3.3]undecanyl.

[0068] The term "cycloalkenyl" as used herein alone or as part of another group includes partially unsaturated cyclic hydrocarbon groups containing one or two double bonds, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl systems, and having one to three rings as part of the ring system, containing a total of 4 to 12 carbons, preferably 5 to 10 carbons. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexanediyl and cycloheptanediyl.

[0069] The term "aryl" as used herein alone or as part of another group refers to a monocyclic or bicyclic aromatic group containing 6 to 10 carbons in the ring portion, such as phenyl or naphthyl (including 1-naphthyl and 2-naphthyl), and optionally containing 1 to 3 additional fused carbocyclic rings, such as cycloalkyl. Examples of aryl groups are phenyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl.

[0070] The term "heterocyclyl" as used herein alone or as part of another group refers to a 5-, 6-, or 7-membered saturated or partially unsaturated ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen, and / or sulfur, which may optionally be fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl ring. The heterocyclyl group is linked via a carbon atom or a heteroatom.

[0071] The term "heteroaryl" as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur, which ring may be optionally fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl ring. When a heteroaryl group is fused to an aryl, it is referred to as a "bicyclic heteroaryl."

[0072] The term "glycosyl" as used herein refers to 1-O-β-D-galactopyranosyl (galactose), 1-O-β-D-glucopyranosyl (glucose) and 1-O-α-D-glucopyranosyl-α-D-glucopyranosyl (trehalose).

[0073] The term "functional partner" refers to one or more compounds (e.g., genes or proteins) that act in a system to support a function. A functional partner can function through one or more intermediates (e.g., genes, small molecules, or proteins).

[0074] The term "dendrites" refers to the branched protoplasmic extensions of neurons that transmit electrochemical stimuli received from other neurons to the cell body or to the neuronal soma of the neuron from which the dendrites project. Electrical stimuli are transmitted to the dendrites by upstream neurons (usually via their axons) via synapses located at various locations throughout the dendritic tree. Dendrites appear to be capable of plastic changes during adulthood in animals, including invertebrates. Neuronal dendrites have various compartments known as functional units that can compute incoming stimuli. These functional units are involved in processing inputs and are composed of dendritic subdomains such as spines, branches, or groupings of branches. Thus, plasticity resulting in changes in dendritic structure will affect information transmission and processing in the cell. During development, the morphology of dendrites is shaped by intrinsic programs within the genome of the cell and extrinsic factors such as signals from other cells. However, during adulthood, extrinsic signals become more influential and induce greater changes in dendritic structure than do intrinsic signals during development.

[0075] The term "Post-Traumatic Stress Disorder" or "PTSD" refers to a mental and behavioral disorder that can develop due to exposure to a traumatic event, such as sexual assault, war, car crashes, violence, etc. Symptoms may include upsetting thoughts, feelings, or dreams related to the event, mental or physical distress in response to trauma-related cues, attempts to avoid trauma-related cues, changes in the way a person thinks or feels, and an increased fight-or-flight response. PTSD causes biochemical changes in the brain and body that are different from other mental disorders, such as major depression.

[0076] The term "traumatic brain injury" or "TBI" refers to injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury [mTBI / concussion] to severe head trauma), mechanism (closed or penetrating head injury), or other features (e.g., occurrence at a specific location or over a widespread area). TBI can lead to temporary or permanent impairment of cognitive, physical, and psychosocial functioning. TBI is not a single pathophysiological event, but a complex disease process, and causes structural damage and functional impairment due to both primary and secondary injury mechanisms. Primary injury occurs upon exposure to the external force and is the result of immediate mechanical disruption of brain tissue, including contusion, damage to blood vessels (hemorrhage), and axonal shearing, in which the axons of neurons are stretched and torn. Secondary injury occurs minutes to months after the primary injury and is the result of a cascade of metabolic, cellular, and molecular events that ultimately lead to brain cell death, tissue damage, and atrophy.

[0077] The term "alcoholism" refers to a chronic medical condition that usually involves current or past excessive drinking, a strong craving for alcohol, continued use despite recurrent problems related to drinking, and an inability to control alcohol consumption.

[0078] The term "multiple sclerosis" or "MS" refers to an inflammatory, demyelinating disease of the central nervous system (CNS) that involves complex interactions between the immune system and nerve cells.

[0079] The term "neurological disorders" broadly refers to disorders of the nervous system. Neurological disorders can affect the brain as well as nerves throughout the body and spinal cord. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can produce a range of symptoms. Neurological disorders include, for example, acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, epilepsy and seizures, Guillain-Barre syndrome, headaches, head injuries, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

[0080] The term "transcriptional control" refers to the means by which cells regulate the conversion of DNA to RNA (transcription), thereby regulating gene activity. A single gene can be regulated in a variety of ways, from changing the number of copies of the transcribed RNA to controlling the time at which the gene is transcribed. This control allows the cell or organism to respond to a variety of intracellular and extracellular signals, thus initiating a response. Transcription factors are proteins that bind to specific DNA sequences to regulate the expression of a given gene.

[0081] The term "oxytocin" or "OT" refers to a nonapeptide synthesized by magnocellular neurons located in the supraoptic (SON) and periventricular (PVN) nuclei of the hypothalamus. It exerts a wide variety of central and peripheral effects. However, its best known and most established role is the stimulation of uterine contractions during parturition and milk secretion during lactation. Oxytocin also influences cardiovascular regulation and various social behaviors. All of the actions of OT are mediated by one type of OT receptor (OTR). This is a transmembrane receptor that belongs to the G protein-coupled receptor superfamily. The main signaling pathway is the Gq / PLC / Ins3 pathway, but MAPK and RhoA / Rho kinase pathways are also activated, contributing to increased prostaglandin production and direct contractile effects on uterine myocytes.

[0082] The terms "protein fosB", "FosB", "G0 / G1 switch regulatory protein 3" or G0S3" refer to the protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene. The FOS gene family includes four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD) thereby forming the transcription factor complex AP-1. Thus, FOS proteins have been implicated in the regulation of cell proliferation, differentiation, and transformation.

[0083] The term "brain-derived neurotrophic factor", "BDNF", or "ablineurin" refers to the protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which is related to the canonical nerve growth factor. Neurotrophic factors are found in the brain and periphery. FOS, JUN, BDNF, CDC42, and CCL2 mediate cohort activity of upstream interactions. The Fos gene family includes four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. Thus, FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of the FOS gene has also been associated with apoptotic cell death.

[0084] The term "c-Jun" refers to the protein that, in humans, is encoded by the JUN gene. c-Jun combines with c-fos to form the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39, and only later was it rediscovered as the product of the JUN gene. c-Jun was first discovered as an oncogenic transcription factor. The proto-oncogene c-Jun is the cellular homologue of the viral oncoprotein v-Jun (P05411). Human JUN encodes a protein highly similar to a viral protein that directly interacts with specific target DNA sequences to regulate gene expression.

[0085] The term "brain-derived neurotrophic factor," "BDNF," or "abrineurin" refers to the protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which is related to canonical nerve growth factor.

[0086] The term "CDC42" or "cell division control protein 42 homolog" refers to a protein involved in cell cycle regulation. Human Cdc42 is a small GTPase of the Rho family that regulates signal transduction pathways that control diverse cellular functions, including cell morphology, cell migration, endocytosis and cell cycle progression.

[0087] The term "CCL2", "chemokine (CC motif) ligand 2" or "monocyte chemoattractant protein 1 (MCP1)" or "small molecule inducible cytokine A2" refers to a small cytokine that belongs to the CC chemokine family. CCL2 recruits monocytes, memory T cells, and dendritic cells to sites of inflammation caused by either tissue injury or infection. CCL2 has been implicated in the pathogenesis of several diseases characterized by monocytic infiltration, such as psoriasis, rheumatoid arthritis, and atherosclerosis.

[0088] Neuroplasticity, also known as neural plasticity or brain plasticity, is the ability to change neural networks in the brain through growth or reorganization. These changes range from individual neuronal pathways making new connections to systematic adjustments such as cortical remapping. Examples of neuroplasticity include changes in circuits and networks resulting from learning novel skills, environmental influences, practice, and mental stress. Activity-dependent plasticity may have important implications for healthy development, learning, memory, and recovery from brain injury.

[0089] The term "STRING" refers to a graphical representation of the relationships between genes or proteins. Functional connections between proteins can often be inferred from the genomic connections between the genes that encode them; groups of genes required for the same function tend to show similar species coverage, are often located close together on the genome (in prokaryotes), and tend to be involved in gene fusion events. The database STRING is a precomputed global resource for the exploration and analysis of these connections. Because the three types of evidence are conceptually distinct and the number of predicted interactions is extremely large, it is essential to be able to assess and compare the significance of individual predictions. Thus, STRING contains a unique scoring framework based on benchmarking the different types of connections against a common reference set, combined into a single confidence score for each prediction. The graphical representation of the inferred network, weighted by protein interactions, provides a high level of functional connectivity and facilitates the analysis of modularity in biological processes.

[0090] The term "dendritic branching" or "dendritic branching" refers to the multi-step biological process by which neurons form new dendritic trees and branches to generate new synapses. This capacity for dendritic growth is thought to play a role in learning and memory formation.

[0091] The term "thiamine" or "vitamin B1" refers to an essential nutrient that functions as a cofactor for a number of enzymes, mainly localized in mitochondria. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids, while others are part of the antioxidant mechanism. The brain is extremely vulnerable to thiamine deficiency due to its great dependency on mitochondrial ATP production. This is more evident during periods of rapid growth (i.e., perinatal period and in children), when thiamine deficiency is usually associated with either nutritional disorders or genetic defects. Thiamine deficiency contributes to a multitude of conditions ranging from mild neurological and psychiatric symptoms (confusion, memory loss, and sleep disorders) to severe encephalopathy, ataxia, congestive heart failure, muscle spasms, and even death.

[0092] The term "subject" or "patient" refers to any single animal, more preferably a mammal (non-human animals, e.g., dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. Most preferably, the patient herein is a human.

[0093] The term "pharmaceutically acceptable carrier" as used herein refers to any solvent, dispersion medium, coating, isotonic agent, absorption retardant, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplementary, additional, or enhanced therapeutic effects.

[0094] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers.

[0095] The term "prevention" as used herein means any action whereby the onset of a disease is inhibited or delayed.

[0096] The terms "treating" or "treatment" refer to one or more of: (1) inhibiting the disease (i.e., preventing further progression of the pathology and / or symptomology); and (2) ameliorating the disease, such as reducing the severity of the disease (i.e., reversing the pathology and / or symptomology).

[0097] The term "administration" refers to the introduction of a certain amount of a predetermined substance into a patient by a particular suitable method. The compositions disclosed herein can be administered via any of the common routes of administration, such as, but not limited to, inhalation, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, pulmonary, or rectal administration, so long as it can reach the target tissue.

[0098] All numerical designations, including ranges, such as pH, temperature, time, and molecular weight, should be understood as approximations, in accordance with the practice in the art. As used herein, the term "about" can imply a variation of (+) or (-) 1%, 5% or 10% of the stated amount, as appropriate in a given context. Although not necessarily expressly stated, it is understood that the reagents described herein are merely exemplary and are equivalent to those known in the art.

[0099] Many known and useful compounds and the like can be found in Remington's Pharmaceutical Sciences (13th Ed), Mack Publishing Company, Easton, PA, a standard text for various types of administration. As used herein, the term "formulation" refers to a combination of at least one active ingredient and one or more other ingredients, also commonly referred to as excipients, which may be independently active or inactive. The term "formulation" may or may not refer to a pharma- ceutically acceptable composition for administration to humans or animals, and may include compositions that are intermediates useful for storage or research purposes.

[0100] Other technical terms used herein have their ordinary meaning in the art in which they are used, as exemplified by various technical dictionaries. The specific values ​​and configurations discussed in these non-limiting examples may vary and are mentioned merely to describe at least one embodiment and are not intended to limit their scope.

[0101] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present technology as claimed. Additional features and advantages of the present technology will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the present technology. The advantages of the present technology will be realized and attained by the structures particularly pointed out in the description and claims hereof.

[0102] Somahal One embodiment is a compound of formula I, or an analog thereof (also referred to as "Somahol"), which is a compound developed through the analysis of a combination of multi-omic and bioinformatics tools including protein-protein interactions, convolutional neural networks, pathway modeling and target receptor site activation studies. [ka] *IUPAC name: (4Z)-4-{N-[(4-amino-2-methylpyrimidin-5-yl)methyl]formamido}-5-{[(2Z)-3-{N-[(4-amino-2-methylpyrimidin-5-yl)methyl]formamido}-6-[(2-{[2-(4-hydroxy-1H-indol-3-yl)ethyl](methyl)amino}propanoyl)oxy]hex-2-en-2-yl]disulfanyl}hex-4-en-1-yl 2-{[2-(4-hydroxy-1H-indol-3-yl)ethyl](methyl)amino}propanoate)

[0103] Structure and synthesis Embodiments include methods of synthesis of Somahal and embodiments of Somahol.Embodiments include methods of synthesis of compounds of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3 and analogs thereof.

[0104] [ka] Compounds A2 and B2 25 mg of indole was charged to a 14 mL open test tube with 3 mL of toluene and 1 mL of acetone and 20 μL of acetic acid. The reaction mixture was heated to reflux temperature for 30 minutes. After 30 minutes, the reaction mixture was allowed to cool, 25 mg of sodium borohydride was added as a solid, and the mixture was stirred for 1 hour. 5 mL of water was added to extract the reaction mixture. The top layer was collected and dried over sodium sulfate, then concentrated under reduced pressure to a brown oil, which was purified by silica gel chromatography (Isco Combiflash, 12 g, Redisep Gold, ethyl acetate, heptane gradient, 0-100% ethyl acetate over 15 minutes) to give 21 mg of the desired isopropylated amine product.

[0105] The product fractions were then combined and concentrated under reduced pressure (SpeedVac) and the resulting oil was used in the screen.

[0106] [ka] Compounds D2 and E2 25 mg of indole was charged to a 14 mL open test tube with 3 mL of toluene and 1 mL of aldehyde and 20 μL of acetic acid. The reaction mixture was heated to reflux temperature for 30 minutes. After 30 minutes, the reaction mixture was allowed to cool. 5 mL of water was added to extract the reaction mixture. The top layer was collected and dried over sodium sulfate, then concentrated under reduced pressure to a brown oil, which was purified by silica gel chromatography (Isco Combiflash, 120 g, Redisep Gold, ethyl acetate, heptane gradient, 0-100% ethyl acetate over 15 minutes) to give 10 mg of the desired tricyclic indole product.

[0107] The product fractions were then combined and concentrated under reduced pressure (SpeedVac) and the resulting oil was used in the screen.

[0108] [ka] compound 2 1.57 g of bromoacetyl chloride was charged to an addition funnel along with 5 mL of dichloromethane and attached to a 50 mL three-necked round bottom flask containing 1.47 g of 4-methoxyindole (1) dissolved in 15 mL of dichloromethane. 75 mg of aluminum trichloride was added as a solid and the reaction mixture was purged with nitrogen and stirred at room temperature for 30 minutes. The bromoacetyl chloride solution was then added dropwise to the stirred reaction mixture over 30 minutes and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then tested for completion and 15 mL of 0.1 M sodium potassium tartrate was added via syringe and the mixture was stirred for an additional 5 minutes before being transferred to a separatory funnel.

[0109] The organic layer was then extracted with 15 mL of saturated brine solution, collected and dried over sodium sulfate. The solvent was removed by rotary evaporation and the solution was purified by silica gel chromatography (Isco Combiflash, 120 g, Redisep Gold, ethyl acetate, heptane gradient, 0-100% ethyl acetate over 15 min). The main product fraction was collected and concentrated by rotary evaporation, at which point the product precipitated after removal of the ethyl acetate. The product was then filtered off, washed with 10 mL of heptane and dried under reduced pressure before use to give 1.95 g of compound 2 (73%).

[0110] Compounds C2, A3, B3 and E3 In a 1 dram vial equipped with a stir bar, 50 mg of compound 2 dissolved in 500 uL of n-methylpyrrolidone was combined with 4 equivalents of the amine and charged all at once. The reaction mixture was heated to 60° C. in an aluminum heating block with stirring and determined to be complete after 3 hours as tested by RP-C18 UPLC.

[0111] The reaction was quenched by the addition of 2 mL of water and the mixture was transferred to a separatory funnel where 10 mL of ethyl acetate, 3 mL of 0.1 M NaOH were added and the organic layer was extracted, followed by 5 mL of saturated brine solution. The organic layer was then dried over sodium sulfate and the mixture was concentrated by rotary evaporation where it was purified by silica gel flash chromatography (Isco Combiflash, 12 g, Redisep Gold, ethyl acetate, heptane gradient, 0-100% ethyl acetate over 15 min).

[0112] The product fractions were then combined and concentrated under reduced pressure (SpeedVac) and the resulting oil was used in the screen.

[0113] [ka] Compound F2 23 mg of the starting product (referenced above as "1") was charged to a 14 mL open test tube with 3 mL of toluene, 15 mg of 2 (above), and 20 uL of acetic acid. The reaction mixture was heated to reflux temperature for 30 minutes. After 30 minutes, the reaction mixture was allowed to cool, after which 25 mg of sodium borohydride was added as a solid and the mixture was stirred for 1 hour. 5 mL of water was added to extract the reaction mixture. The top layer was collected and dried over sodium sulfate, then concentrated under reduced pressure to a brown oil, which was purified by silica gel chromatography (Isco Combiflash, 12 g, Redisep Gold, ethyl acetate, heptane gradient, 0-100% ethyl acetate over 15 minutes) to give 18 mg of the desired amine product, 3 (shown above).

[0114] The product fractions were then combined and concentrated under reduced pressure (SpeedVac) and the resulting oil was used in the screen.

[0115] [ka] Compounds G2, H2, C3, D3 The embodiment also includes a method for the synthesis of compounds G2, H2, C3 and D3. The compounds were prepared by methods known in the art (see, for example, WO 2021 / 176599A1). Briefly, 0.5 mmol of arylhydrazine, 0.5 mmol of ketone, 4 mL of ethanol and 6 equivalents of 37% HCl were charged into an 8 mL sealed vial. The reaction mixture was heated to 100° C. overnight. The next day, the solvent was removed by rotary evaporation and the compound was dissolved in 10 mL of dichloromethane and extracted twice with 10 mL of 0.1 M HCl. The dichloromethane layer was dried over sodium sulfate and concentrated to an oil.

[0116] The oil was purified by silica gel flash chromatography (Isco Combiflash, 12 g, Redisep Gold, methanol, dichloromethane (both containing 2% ammonium hydroxide) gradient, 0-50% methanol over 15 min.) The product fractions were then combined and concentrated under reduced pressure (SpeedVac) and the resulting oil was used in screening.

[0117] analogue The embodiments also include analogs of Somahol. Figure 1 shows the structure of Somahol with the atoms numbered. The molecule may contain five or more additional methyl groups between carbons 6 and 7 and between 43 and 44. The oxygens at moieties 10 and 48 may be replaced by hydroxyl groups. The sulfur may be replaced by phosphorus. Alternatively, the sulfur may be replaced by a triphosphate backbone attached to a fatty acid chain, or the sulfur may be replaced by a lipoprotein in various forms, such as magnesium-impregnated cholesterol. Additionally, the carbon (54 and 55) covalent bond may be replaced by an ionic bond using a salt moiety such as potassium and phosphoric acid or other salt repeat at position 54. Functional groups at positions beyond 54 may be attached directly to the phosphate center of another repeat.

[0118] Embodiments also include prodrugs of the therapeutic molecules disclosed herein.

[0119] In one embodiment, one or more therapeutic molecules described herein can stimulate synaptic neuroplasticity. Synaptic neuroplasticity can be defined as the tendency of synapses to become stronger or weaker in response to changes in presynaptic activity. This plasticity often manifests as a change in the number of synapses on a particular neuron, thereby altering neural connections throughout the brain on a long-term scale. Based on molecular mechanisms obtained from biopsied brain tissue, applicants have identified mechanisms for remodeling the addicted brain and resolving addiction. Applicants propose that the compound of formula I (i.e., Somahol) has beneficial effects on the brain, which may promote remodeling of the limbic system.

[0120] Without being bound by theory, applicants propose that the molecule affects upstream regulators of FOS, JUN, BDNF, CDC42 and CCL2 through the activity of a cohort of upstream interactions. These direct upstream interactions are a cohort of all 5-HT receptor agonism via direct binding, Gal2 agonism, allosteric regulation of acetyl-CoA metabolism, including protein regulatory acetylation and acetylcholine biosynthesis, increased MDH2 encoding via enhanced acetylation, and agonism of the THDP pathway via coenzyme mimicry.

[0121] Based on Applicants' mechanistic model, the downstream effects of these interactions result in homeostasis of stimulation of FosB, JUN, and BDNF, reducing the relative abundance of CCL2 through the combined activation of 5-HT7R, 5-HT2AR, oxytocin, G-coupled proteins, and mitochondrial stimulation, as well as downstream feedback activities including facilitation of oxytocin, acetylcholine, and dopamine.

[0122] Thus, in one embodiment, Somahol (or other therapeutic molecules) can modulate one or more G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous system, such as the 5-HT receptor. In some embodiments, Somahol (or other therapeutic molecules) affects one or more proto-oncogenes, such as FOS, JUN, BDNF, CDC42, or CCL2. In one embodiment, Somahol modulates the levels of oxytocin, acetylcholine, and / or dopamine.

[0123] These combined activities are involved in increasing neuroplasticity.For example, the therapeutic molecules described herein can show both allosteric and direct binding mechanisms to effectively improve dendrite formation through Ga12 signaling, including CDC42 stimulation.The molecules can show effects on enhanced neurohormonal signaling, including the above-mentioned effects on oxytocin, acetylcholine and dopamine, especially in limbic cortex, cingulate gyrus, raphe nucleus, parahippocampal gyrus, dentate gyrus, hippocampus, subiculum, amygdala, septum and hypothalamus.

[0124] route An essential property of the nervous system is its ability to remodel functional connectivity in response to physiological and environmental stimuli. Endogenous signals, including neuropeptides, govern nervous system plasticity. In particular, oxytocin has been recognized for its role in mediating activity-dependent circuit changes. These oxytocin-dependent changes occur at the synaptic level, consequently shaping the cellular composition of the circuits.

[0125] Figure 2 shows the oxytocin signaling pathway. Alterations in oxytocin signaling may disrupt neuronal maturation and have short-term and long-term pathological consequences. Abnormal regulation of oxytocin signaling is associated with the pathogenesis of neurodevelopmental disorders. Recent investigations have shown synaptic dysfunction in neurodevelopmental disorders. Thus, pathogenic mechanisms may be targets for therapeutic intervention.

[0126] The neurotransmitter serotonin (5-HT) plays a major role in behavioral and psycho-psychological functions such as behavioral inhibition, appetite suppression, mood, cognitive function, thermoregulation, and addictive behaviors. The serotonin (5-HT) neurotransmitter system is of particular interest, as multiple 5-HT receptors are thought to play a key role in alcohol and drug self-administration and the development of drug dependence. Serotonin receptor agonists are agonists of one or more serotonin receptors. They activate serotonin receptors in a manner similar to serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter and hormone that is the endogenous ligand of serotonin receptors. Figure 3 shows 5-HT receptors and associated actions. Somahol selectively activates 5-HT7 receptors (i.e., 5-HT7R), which ultimately activates dendritic extensions.

[0127] Thus, in some embodiments, Somahol (or other therapeutic molecules) can modulate one or more of behavioral inhibition, appetite suppression, mood, cognitive function, thermoregulation, and addictive behaviors. In other embodiments, Somahol can be administered to treat addiction, alcoholism, and / or to prevent the development of drug dependency.

[0128] Somahol was investigated for its agonist potential. i Values ​​were observed at the 5-HT2B and 5-HT7 receptors. Various 5-HT receptor agonisms (shown in Table 1 below) are associated with DJ-1 (PARK7) and other parts of the molecule that show high binding affinity with amyloid beta (a4). The molecule also increases the relative abundance of the proteins MARCS, VATA, VATB, THY1 and HPLN1 through mechanisms currently being investigated. [Table 1]

[0129] 5-HT7 receptor is involved in thermoregulation, circadian rhythm, learning and memory, as well as sleep.This receptor is also speculated to be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.Figure 2 is a schematic diagram of the signal transduction pathway regulated by 5-HT7 receptor.The left part lists the effect mediated by Gs protein.Similarly, the right part lists the process of G12-mediated signal transduction.

[0130] In some embodiments, Somahol can be administered to a patient as a 5-HT7 receptor agonist. In some embodiments, Somahol can regulate circadian rhythms, learning and memory, sleep, mood regulation and / or depression.

[0131] In some embodiments, the therapeutic molecule disclosed herein can be administered to a patient as a 5-HT7 receptor agonist. In some embodiments, the molecule can regulate circadian rhythm, learning and memory, sleep, mood regulation and / or depression. The molecule can be A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and / or E3.

[0132] RNase 1 Pancreatic-type ribonuclease is an enzyme that in humans is encoded by the RNase 1 gene. The gene encodes a member of the pancreatic type of secretory ribonuclease, a subset of the ribonuclease A superfamily. The encoded endonuclease cleaves internal phosphodiester RNA bonds 3' to pyrimidine bases. Figure 4 shows the interaction of RNase 1 with neighboring genes.

[0133] Functional partners of RNase 1 include: 1. RNH1: ribonuclease inhibitor; a ribonuclease inhibitor that inhibits RNase 1, RNase 2, and ANG. This gene may be involved in redox homeostasis. 2. SE14L2: SEC14-like protein 2; a carrier protein. It binds several hydrophobic molecules and facilitates their movement between different cellular sites. It binds with high affinity to α-tocopherol. It also binds with weaker affinity to other tocopherols and tocotrienols. It may have transcriptional activator activity through its binding to α-tocopherol. It probably recognizes and binds several squalene structures, suggesting that it may regulate cholesterol biosynthesis by increasing the movement of squalene into metabolically active pools in cells. 3. ANXA5 (Annexin A5) This protein is an anticoagulant protein that functions as an indirect inhibitor of the thromboplastin-specific complex involved in the blood coagulation cascade. 4. RNase T2 (Ribonuclease T2) This protein has ribonuclease activity, with higher activity at acidic pH. It is also involved (by analogy) in the lysosomal degradation of ribosomal RNA and may be involved in cellular RNA catabolism. 5. MB (myoglobin) MB acts as an oxygen reserve and promotes oxygen transport within muscles. 6.C2orf49 (Ashwn; chromosome 2 open reading frame 49). 7.ALB(Serum Albumin)It is the major protein of plasma and has good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is to regulate the oncotic pressure of blood. It is the main zinc transporter in plasma and normally binds about 80% of all plasma zinc. 8. DNase 1 (Deoxyribonuclease 1) Among other features, DNase 1 appears to be involved in apoptotic cell death. It specifically binds to G-actin and blocks actin polymerization. 9. CYCS (Cytochrome c; Electron-Carrying Protein) The heme group of the oxidized form of cytochrome c can accept electrons from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transports these electrons to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron transport chain. 10. P4HB (Protein Disulfide Isomerase)This multifunctional protein catalyzes the formation, cleavage and transfer of disulfide bonds. At the cell surface it appears to function as a reductase that cleaves disulfide bonds in proteins attached to the cell. Thus, it may result in structural modifications of extracellular surface proteins. Inside the cell, it appears to form / rearrange disulfide bonds in nascent proteins. At high concentrations, it functions as a chaperone that inhibits aggregation of misfolded proteins. At low concentrations, it promotes aggregation (anti-chaperone activity).

[0134] Thus, in some embodiments, Somahol (or other therapeutic molecules disclosed herein) may be administered to modulate RNase 1 levels and / or activity. In some embodiments, functional partners of RNase 1 include one or more of RNH1, SE14L2, ANXA5, RNASET2, MB, C2orf49, ALB, DNASE1, CYCS, and P4HB. Figure 1 shows the interaction of RNase 1 with neighboring genes or "functional partners."

[0135] CCL2 Chemokine (CC motif) ligand 2 (CCL2) is also called monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. It attracts monocytes and basophils, but not neutrophils or eosinophils. It also enhances monocyte antitumor activity and has been associated with the pathogenesis of diseases characterized by monocytic infiltration, such as psoriasis, rheumatoid arthritis or atherosclerosis. Recent studies have shown that CCL2-treated neural stem cells exhibited a significantly enhanced ability of self-renewal, proliferation and neuronal differentiation. Similarly, Figure 5 shows the interaction of CCL2 with neighboring genes.

[0136] Functional partners of CCL2 include: 1. CCR2 (CC chemokine receptor type 2; receptor for CCL2, CCL7 and CCL13 chemokines). CCR2 is the receptor for the beta-defensins DEFB106A / DEFB106B. It transmits signals by increasing intracellular calcium ion levels (by similarity). Upon CCL2 ligation, it mediates chemotaxis and migration induction by activation of the PI3K cascade, the small G protein Rac and lamellipodial protrusions. 2. IL10 (Interleukin-10) IL10 suppresses the synthesis of multiple cytokines produced by activated macrophages and by helper T cells, including IFNγ, IL-2, IL-3, TNF and GM-CSF. 3. IL4 (Interleukin-4) IL4 is involved in at least some B cell activation processes as well as activation processes of other cell types. It is a costimulatory molecule for DNA synthesis. It induces the expression of class II MHC molecules on resting B cells. It enhances both the secretion and cell surface expression of IgE and IgG1. It also regulates the expression of the low affinity Fc receptor for IgE (CD23) on both lymphocytes and monocytes. It also positively regulates IL31RA expression in macrophages. 4.IL6 (Interleukin-6)IL6 is a cytokine with a wide range of biological functions. It is a potent inducer of the acute phase response. It plays a key role in the terminal differentiation of B cells into Ig-secreting cells and is involved in lymphocyte and monocyte differentiation. It acts on B cells, T cells, hepatocytes, hematopoietic progenitor cells and cells of the CNS. It is required for the generation of T(H)17 cells. It also acts as a myokine, is released into the bloodstream after muscle contraction, and acts to enhance the breakdown of fats and oils, and to improve insulin resistance. 5. STAT3 (Signal Transducer and Activator of Transcription 3) STAT3 is a signal transducer and transcriptional activator that mediates cellular responses to interleukins, KITLG / SCF, (LEP) and other growth factors. Upon activation, it recruits coactivators such as NCOA1 or MED1 to the promoter regions of target genes. It can mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. It binds to interleukin-6 (IL-6) response elements identified in the promoters of various acute phase protein genes. It is activated by IL31 via IL31RA. 6. IL13 (Interleukin-13; Cytokine) IL3 suppresses inflammatory cytokine production. It synergizes with IL2 in regulating interferon gamma synthesis and may be important in regulating inflammatory and immune responses. It positively regulates IL31RA expression in macrophages. 7. CXCL8 (Interleukin-8)IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to inflammatory stimuli. IL-8(6-77) has 5-10 times higher activity for neutrophil activation, IL-8(5-77) has increased activity for neutrophil activation, and IL-8(7-77) has higher affinity for the receptors CXCR1 and CXCR2 compared to IL-8(1-77). 8. JUN (transcription factor AP-1) JUN is a transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'. When phosphorylated by HIPK3, it promotes NR5A1 activity, leading to increased steroidogenic gene expression upon stimulation of the cAMP signaling pathway, and is involved in the activation KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells. It binds to the USP28 promoter in colorectal cancer (CRC) cells and is a basic leucine zipper protein. 9.TNF This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is primarily secreted by macrophages. It binds to, and thus functions through, its receptors TNFRSF1A / TNFR1 and TNFRSF1B / TNFBR. This cytokine is involved in the regulation of a wide range of biological processes, including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been associated with a variety of diseases, including autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis, ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in this gene affect susceptibility to cerebral malaria, septic shock, and Alzheimer's disease. Knockout studies in mice also suggested a neuroprotective function for this cytokine. 10.FOS The Fos gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. Thus, FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of FOS genes has also been associated with apoptotic cell death.

[0137] Thus, in some embodiments, Somahol (or other therapeutic molecules disclosed herein) may be administered to modulate CCL2 levels and / or activity. In some embodiments, functional partners of CCL2 include one or more of CR2, IL10, IL4, IL6, STAT3, IL13, CXCL8, JUN, TNF, and FOS.

[0138] FOSB The protein fosB, also known as FOS, FosB and G0 / G1 switch regulatory protein 3 (G0S3), is a protein encoded in humans by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene. Figure 5 shows FOS interactions with neighboring genes. Figure 6 shows FosB interactions with neighboring genes.

[0139] FOSB's functional partners include: 1.JUN This gene is a putative transforming gene of avian sarcoma virus 17. It encodes a protein highly similar to viral proteins and directly interacts with specific target DNA sequences to regulate gene expression. The gene is intronless and maps to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies. 2. JUND The protein encoded by this intronless gene is a member of the JUN family and a functional component of the AP1 transcription factor complex. The protein has been proposed to protect cells from p53-dependent senescence and apoptosis. The use of alternative translation start sites results in the production of distinct isoforms. 3.JUNB Transcription factor jun-B; a transcription factor involved in regulating gene activity following primary growth factor response. Binds to the DNA sequence 5'-TGA[CG]TCA-3'; belongs to the bZIP family. 4. FOS The Fos gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. Thus, FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of FOS genes has also been associated with apoptotic cell death. 5.CDK5 This gene encodes a proline-targeted serine / threonine kinase that is a member of the cyclin-dependent kinase protein family. Unlike other members of the family, the protein encoded by this gene does not directly regulate cell cycle regulation. Instead, the protein is expressed at high levels in mammalian postmitotic central nervous system neurons and functions in a wide range of processes such as neuronal migration through phosphorylation of proteins required for synaptic plasticity and cytoskeleton formation, endocytosis and exocytosis, and apoptosis. In humans, allelic variants of this gene that result in undetectable levels of protein are associated with lethal autosomal recessive dysentery-7. Alternative splicing gives rise to multiple transcript variants. 6.EP300 This gene encodes the adenovirus E1A-associated cellular p300 transcriptional coactivator protein. It functions as a histone acetyltransferase that regulates transcription through chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP gene regulation by specifically binding to phosphorylated CREB protein. This gene has also been identified as a coactivator of HIF1A (hypoxia-inducible factor 1 alpha) and is therefore involved in the stimulation of hypoxia-inducible genes such as VEGF. Defects in this gene are responsible for Rubinstein-Taebi syndrome and may also contribute to epithelial cancer. 7.MAFG Globin gene expression is regulated through the nuclear transcription factor erythroid-2 (NFE2) sequence enhancer located in an enhancer-like locus control region located several kb upstream of the α and β gene clusters (reviewed in Blank et al., 1997 [PubMed 9166829]). The NFE2 DNA binding activity consists of a heterodimer containing the ubiquitous small Maf protein (MafF, MIM604877; MafG; or MafK, MIM600197) and the tissue-restricted protein p45 NFE2 (MIM601490). Both subunits are members of the activator protein 1-like superfamily of basic leucine zipper (bZIP) proteins. 8.EGR1 The protein encoded by this gene belongs to the EGR family of C2H2-type finger proteins. It is a nuclear protein and functions as a transcription factor. The products of the target genes it activates are required for differentiation and mitogenesis. Studies suggest that it is a tumor suppressor gene. 9. MYC (Myc proto-oncogene protein) MYC is a transcription factor that binds DNA in a nonspecific manner but also specifically recognizes the core sequence 5'-CAC[GA]TG-3'. It activates the transcription of growth-related genes. It binds to the VEGFA promoter and promotes VEGFA production and subsequent angiogenesis by sprouting; it is a basic helix-loop-helix protein. 10.HIST1H2BA Histones are basic nuclear proteins involved in the nucleosomal structure of the chromosome fiber in eukaryotes. A nucleosome consists of approximately 146 bp of DNA wrapped around a histone octamer consisting of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of the DNA between the nucleosomes and the linker histone H1 to form higher order chromatin structures. This gene is intronless and encodes a replication-dependent histone that is a testis / sperm specific member of the histone H2B family. The transcript of this gene contains a palindromic termination sequence.

[0140] Thus, in some embodiments, Somahol (or other therapeutic molecules disclosed herein) may be administered to modulate FosB levels and / or activity. In some embodiments, functional partners of FosB include one or more of JUN, JUND, JUNB, FOS (i.e., another member), CDK5, EP300, MAFG, EGR1, MYC, and HIST1H2BA.

[0141] SLC39A8 The SLC39A8 gene encodes a member of the SLC39 family of solute carrier genes, which exhibits structural features of zinc transporters. The encoded protein is glycosylated and found in cell membranes and mitochondria, where it functions in the intracellular import of zinc at the onset of inflammation. It is also thought to be the primary transporter of the toxic cation cadmium, which is found in cigarette smoke. Multiple transcript variants encoding different isoforms have been found in this gene. Additional alternatively spliced ​​transcript variants of this gene have been reported, but their full-length nature is unknown. Figure 7 shows SLC39A8 interacting with neighboring genes.

[0142] Functional partners of SLC39A8 include: 1. SLC30A1 (Zinc Transporter 1) SLC30A1 may be involved in zinc transport out of cells; it belongs to the cation diffusion facilitator (CDF) transporters (TC2.A.4). 2. SLC39A14 (Zinc Transporter ZIP14) SLC39A14 is a widespread metal ion transporter with a preference for zinc uptake. It also mediates the cellular uptake of non-transferrin-bound iron; it belongs to the ZIP transporter (TC2.A.5) family. 3. SLC39A2 This gene encodes a member of the ZIP family of metal ion transporters. The encoded protein functions as a zinc transporter. Mutations in this gene may be associated with susceptibility to carotid artery disease. Multiple transcript variants have been described. 4. SLC39A1 This gene encodes a member of the zinc-iron permease family. The encoded protein localizes to the cell membrane and acts as a zinc uptake transporter. This gene has been linked to prostate cancer, breast cancer, and Alzheimer's disease. Alternative splicing gives rise to multiple transcript variants. 5. SLC39A9 (Zinc Transporter ZIP9) This gene can act as a zinc influx transporter; it belongs to the ZIP transporter (TC2.A.5) family. 6. SLC30A10 This gene is highly expressed in the liver and is inducible by manganese. Its protein product appears to be important in maintaining manganese levels and has a higher specificity for manganese than zinc. Loss-of-function mutations appear to give rise to polymorphic phenotypes, including dystonia and adult-onset parkinsonism. Alternative splice transcript variants have been observed for this gene. 7. SLC30A7 Zinc functions as a cofactor for numerous enzymes, nuclear transcription factors, and hormones, and as an intra- and intercellular signaling ion. Members of the zinc transporter (ZNT) / SLC30 subfamily of cation diffusion facilitators family, such as SLC30A7, enable the cellular efflux of zinc. 8. SLC30A6 This gene encodes a member of a family of proteins that function as zinc transporters. This protein can regulate intracellular levels of zinc in the Golgi and vesicles. Expression of this gene is altered in Alzheimer's disease brain plaques. 9.SLC30A5 This gene encodes a member of the SLC30A / ZnT family of zinc transporter proteins. ZnT proteins mediate both cellular zinc efflux and zinc sequestration in membrane-bound organelles. The encoded protein participates in the early secretory pathway as a heterodimer with zinc transporter 6 and may regulate zinc sequestration in secretory granules in pancreatic beta cells. Alternatively spliced ​​transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene for this gene is located on the long arm of chromosome 19. 10. SLC39A11 Zinc transporter ZIP11; functions as a cellular zinc transporter.

[0143] Thus, in some embodiments, Somahol (or other therapeutic molecules disclosed herein) may be administered to modulate SLC39A8 levels and / or activity. In some embodiments, functional partners of SLC39A8 include one or more of SLC30A1, SLC39A14, SLC39A2, SLC39A1, SLC39A9, SLC30A10, SLC30A7, SLC30A6, SLC30A5, and SLC39A11.

[0144] C9orf135 C9ORF135 is a gene that encodes a 229-amino acid protein. It is located at 9q12.21 on chromosome 9 of the Homo sapiens genome. The protein has a transmembrane domain at amino acids 124–140 and a glycosylation site at amino acid 75. C9orf135 has been associated with neurogenesis. Figure 8 shows C9ORF135 interacting with neighboring genes.

[0145] Functional partners of C9orf135 include: 1. TPRG1 (Tumor Protein P63 Regulated 1) TPRG1 is a protein-coding gene. Diseases associated with TPRG1 include mixed liposarcoma. The key paralog of this gene is TPRG1L. 2. DRICH1 (Aspartic Acid Rich 1) DRICH1 is a protein-coding gene. Diseases associated with DRICH1 include childhood acute lymphoblastic leukemia and retinitis pigmentosa. A key paralog of this gene is C22orf. 3. CCDC42 (Coiled-coil domain-containing protein 42) CCDC42 is required for spermatogenesis. 4. ODF4 This gene encodes a protein that is localized in the outer dense fiber of the tail of mature sperm. This protein is thought to have several important roles in the sperm tail. Alternative splicing gives rise to multiple transcript variants. 5. HDDC2 (HD domain containing 2) This belongs to the HDDC2 family. 6. FAM160B1 (FHIP2A, FHF complex subunit HOOK interacting protein 2A) is a protein-coding gene. FHIP2A-related disorders include syndromic intellectual disability and anlacrimation, achalasia, and mental retardation syndromes. The key paralog of this gene is FHIP2B. 7.IGSF3 The protein encoded by this gene is an immunoglobulin-like membrane protein that contains several type V immunoglobulin-like domains. Mutations in this gene are associated with bilateral nasolacrimal duct obstruction (LCDD). 8.POU51 This gene encodes a transcription factor containing a POU homeodomain that plays an important role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. This gene can be involved in translocations with the Ewing sarcoma gene on chromosome 21, which also results in tumorigenesis. Alternative splicing and the selective use of either AUG or non-AUG translation initiation codons result in multiple isoforms. One of the AUG initiation codons is polymorphic in the human population. Related pseudogenes have been identified on chromosomes 1, 3, 8, 10, and 12. 9. LRCH2 This gene encodes a member of the leucine-rich repeat and calponin homology domain-containing protein family. These family members contain multiple N-terminal leucine-rich repeats in addition to a C-terminal calponin homology domain, a domain that mediates interactions with actin filaments. These proteins are conserved across animal species, and studies of the analogous Drosophila protein indicate a function as a cytoskeletal scaffolding protein. Alternative splicing of this gene gives rise to multiple transcript variants. 10. CLRN3 (Clarin3) CLRN3 is a protein-coding gene. Diseases associated with CLRN3 include Usher syndrome and gastric tubular adenocarcinoma. The key paralog of this gene is CLRN2.

[0146] Thus, in some embodiments, Somahol (or other therapeutic molecules disclosed herein) may be administered to modulate C9orf135 levels and / or activity. In some embodiments, functional partners of C9orf135 include one or more of TPRG1, DRICH1, CCDC42, ODF4, HDDC2, FAM160B1, IGSF3, POU51, LRCH2, and CLRN3.

[0147] ENTPD4 The ENTPD4 gene encodes a member of the apyrase protein family. Apyrase is an enzyme that catalyzes the hydrolysis of nucleotide diphosphates and triphosphates in a calcium- or magnesium-dependent manner. The encoded protein is an endoapyrase and may be involved in nucleotide salvage from lysosomes. Alternative splice transcript variants encoding multiple isoforms have been observed for this gene, which may differ in divalent cation dependency and substrate specificity. Figure 9 shows ENTPD4 interacting with neighboring genes.

[0148] Functional partners of ENTPD4 include: 1.ADSSL1 This gene encodes a member of the adenylosuccinate synthase protein family. The encoded muscle-specific enzyme participates in the purine nucleotide cycle by catalyzing the first step in the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP). Mutations in this gene can cause adolescent-onset distal myopathy. Alternative splicing gives rise to multiple transcript variants. 2. ITPA (inosine triphosphate pyrophosphatase) ITPA is a pyrophosphatase that hydrolyzes the non-standard purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (DITP) and 2'-deoxy-N-6-hydroxylaminopurine triphosphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy and ribose forms. It probably excludes non-standard purines from the RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions. 3.ATIC This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. Mutations in this gene result in AICA-ribosiduria. 4.ENPP3 The protein encoded by this gene belongs to a series of ectoenzymes involved in the hydrolysis of extracellular nucleotides. These ectoenzymes have ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the relevant rat mRNA was found in a subset of immature glial cells and in the digestive tract. The corresponding rat protein was detected in the pancreas, small intestine, colon, and liver. Human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein was detected in uterus, basophils, and mast cells. Two transcript variants, one protein-coding and one non-protein-coding, were found for this gene. 5. ADSS This gene codes for the enzyme adenylosuccinate synthetase, which catalyzes the first step in the conversion of inosine monophosphate to adenosine monophosphate. A pseudogene of this gene is found on chromosome 17. 6.ENPP1 This gene is a member of the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein that contains two identical disulfide-linked subunits. The protein has broad specificity and cleaves a variety of substrates, including the phosphodiester bond of nucleotides and nucleotide sugars and the pyrophosphate bond of nucleotides and nucleotide sugars. The protein functions to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and can also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with "idiopathic" infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. 7.ENTPD6 ENTPD6 is similar to E-type nucleotidases. Nucleotide triphosphate degrading enzymes, such as CD39, mediate the catabolism of extracellular nucleotides. ENTPD6 contains four apyrase conserved domains characteristic of nucleotidyl triphosphate degrading enzymes. Alternative splicing gives rise to multiple transcript variants encoding different isoforms. 8. ENTPD5 The protein encoded by this gene is similar to E-type nucleotidases / ecto-ATPases / apyrases. Nucleotide triphosphate enzymes, such as CD39, mediate the catabolism of extracellular nucleotides. ENTPD5 contains four apyrase conserved domains that are characteristic of nucleotidyl triphosphate enzymes. 9.PKM This gene encodes a protein involved in glycolysis. The encoded protein is pyruvate kinase, which catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate to ADP. This protein has been shown to interact with thyroid hormone and may mediate thyroid hormone-induced cellular metabolic effects. This protein was found to bind Opa protein, a bacterial outer membrane protein involved in gonococcal adhesion in the invasion of human cells, suggesting a role for this protein in bacterial pathogenesis. Several alternatively spliced ​​transcript variants encoding a small number of distinct isoforms have been reported. 10.UMPS This gene codes for uridine 5'-monophosphate synthase. The encoded protein is a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The first reaction is carried out by the N-terminal enzyme orotate phosphoribosyltransferase, which converts orotidine-5'-monophosphate to orotidine-5'-monophosphate. The last reaction is carried out by the C-terminal enzyme OMP decarboxylase, which converts orotidine-5'-monophosphate to uridine monophosphate. Defects in this gene are the cause of hereditary orotic aciduria. Alternative splicing gives rise to multiple transcript variants.

[0149] Thus, in some embodiments, Somahol can be administered to regulate ENTPD4 levels and / or activity. In some embodiments, functional partners of ENTPD4 include one or more of ADSSL1, ITPA, ATIC, ENPP3, ADSS, ENPP1, ENTPD6, ENTPD5, PKM and UMPS.

[0150] OXT Oxytocin is a neuropeptide involved in reproduction and social behavior in animals and humans. Oxytocin operates through both synaptic and cellular plasticity mechanisms to rewire brain circuits to enhance neuronal representation of sensory stimuli. This enhanced sensory salience promotes both the formation and maintenance of complex behaviors. Three oxytocin signaling genes are often associated with human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (oxytocin secretion). This gene encodes a precursor protein that is processed to produce oxytocin and neurophysin I. Oxytocin is a posterior pituitary hormone that is synthesized as an inactive precursor in the hypothalamus along with its carrier protein, neurophysin I. Together with neurophysin, it is packaged into neurosecretory vesicles and transported axonally to nerve terminals in the neurohypophysis where it is stored or secreted into the bloodstream. The precursor appears to be activated while it is transported along the axons to the posterior pituitary. The hormone contracts smooth muscles during parturition and lactation. It is also involved in cognition, tolerance, adaptation and complex sexual and maternal behavior, as well as the regulation of water excretion and cardiovascular function.

[0151] Functional partners of OXT include: 1. OXTR (Oxytocin Receptor; Receptor for Oxytocin) The protein encoded by this gene belongs to the G protein-coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins, which activate the phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during childbirth. 2. NPS (Neuropeptide S) NPS regulates arousal and anxiety. It plays an important appetite suppressant role (by analogy). It binds to its receptor NPSR1 with nanomolar affinity and increases intracellular calcium concentrations. 3. TRH (Prothyrotropin-Releasing Hormone) This gene encodes a member of the thyrotropin-releasing hormone family. Cleavage of the encoded proprotein releases mature thyrotropin-releasing hormone, a tripeptide hypothalamic regulating hormone. The human proprotein contains six thyrotropin-releasing hormone tripeptides. Thyrotropin-releasing hormone is involved in the regulation and release of thyrotropin-stimulating hormone, as well as prolactin. Deficiency of this hormone is associated with hypothalamic hypothyroidism. 4. CCK (Cholecystokinin) This peptide hormone induces gallbladder contraction and release of pancreatic enzymes in the intestine. This gene encodes several members of the gastrin / cholecystokinin protein family. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the peptide hormones cholecystokinin-8, -12, -33, and others. The encoded peptide has been shown to regulate gastric acid secretion and food intake. A sulfated form of cholecystokinin-8 can regulate neuronal activity in the brain. Alternative splicing gives rise to multiple transcript variants. 5.GNRH1 This gene encodes a preproprotein that is proteolytically processed to generate a peptide that is a member of the gonadotropin-releasing hormone (GnRH) peptide family of peptides. Alternative splicing gives rise to multiple transcript variants, at least one of which is secreted and subsequently cleaved to generate gonadoliberin-1 and GnRH-related peptide 1. Gonadodoliberin-1 stimulates luteinization and release of follicle-stimulating hormone, which are important for reproduction. Mutations in this gene are associated with hypogonadotropic hypogonadism. 6.AVP This gene encodes a member of the vasopressin / oxytocin family and a preproprotein that is proteolytically processed to generate multiple protein products. These products include the neuropeptide hormone arginine vasopressin, and two other peptides, neurophysin 2 and copeptin. Arginine vasopressin is a posterior pituitary hormone that is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus. Together with its carrier protein, neurophysin 2, it is packaged into neurosecretory vesicles and transported axonally to nerve endings in the neurohypophysis, where it is stored or secreted into the bloodstream. The precursor is thought to be activated while it is transported along the axons to the posterior pituitary. Arginine vasopressin acts as a growth factor by increasing pH regulation via an acid-base transport system. It has a direct antidiuretic effect on the kidney and also causes vasoconstriction of peripheral blood vessels. The hormone can contract smooth muscle during parturition and lactation. It is also involved in cognition, tolerance, adaptation and complex sexual and maternal behavior, as well as the regulation of water excretion and cardiovascular function. Mutations in this gene cause autosomal dominant neurohypophyseal diabetes insipidus (ADNDI). The gene is located in a gene cluster with the related gene oxytocin on chromosome 20. 7.AVPR1A The protein encoded by this gene acts as a receptor for arginine vasopressin. This receptor belongs to a subfamily of G protein-coupled receptors that includes AVPR1B, V2R, and OXT receptors. Its activity is mediated by G proteins that stimulate the phosphatidylinositol-calcium second messenger system. This receptor mediates cell contraction and proliferation, platelet aggregation, release of clotting factors, and glycogenolysis. 8.HCRT This gene encodes a hypothalamic neuropeptide precursor protein that upon proteolytic processing generates two mature neuropeptides, orexin A and orexin B. Orexin A and orexin B bind to the orphan G protein-coupled receptors HCRTR1 and HCRTR2 and function in the regulation of sleep and wakefulness. The disposition of this neuropeptide may also be involved in feeding behavior, metabolism, and homeostasis. 9.AVPR1B The protein encoded by this gene acts as a receptor for arginine vasopressin. This receptor belongs to a subfamily of G protein-coupled receptors that includes AVPR1A, V2R, and OXT receptors. Its activity is mediated by G proteins, which stimulate the phosphatidylinositol-calcium second messenger system. This receptor is located primarily in the anterior pituitary gland, where it stimulates ACTH release. It is expressed at high levels in ACTH-secreting pituitary adenomas as well as in bronchial carcinoids, which are responsible for ectopic ACTH syndrome. A spliced ​​antisense transcript of this gene has been reported, but its function is unknown. 10.TAC1 This gene encodes four products of the tachykinin peptide hormone family: substance P and neurokinin A, as well as the related peptides neuropeptide K and neuropeptide gamma. These hormones are thought to function as neurotransmitters, interacting with neuroreceptors and smooth muscle cells. They are known to induce behavioral responses and function as vasodilators and secretagogues. Substance P is an antimicrobial peptide with antibacterial and antifungal properties. Multiple transcript variants encoding different isoforms have been found in this gene.

[0152] Thus, in some embodiments, Somahol (or other therapeutic molecules disclosed herein) may be administered to regulate oxytocin levels and / or activity. In some embodiments, functional partners of oxytocin include one or more of OXTR, NPS, TRH, CCK, GNRH1, AVP, AVPR1A, HCRT, AVPR1B, and TAC1.

[0153] How to use Somahol and analogs can be administered in various forms, as is well known in the art, depending on the disorder to be treated and the age, condition and weight of the patient.For example, when the compositions are administered orally, they can be formulated as tablets, granules, powders, or syrups; or for parenteral administration, they can be formulated as injections (for intravenous, intramuscular, or subcutaneous injection), drop injection preparations, or suppositories.Any suitable route or method of administration can be adopted to provide the patient with a therapeutic or prophylactically effective amount of therapeutic peptide. Exemplary routes and methods of administration include parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous, intratumor), oral, topical (nasal, transdermal, intradermal or intraocular), mucosal (e.g., nasal, sublingual, buccal, rectal, vaginal), inhalation, intranodal, intraspinal, intracranial, intraperitoneal, intratracheal, intravesical, intrathecal, intraintestinal, intrapulmonary, intranodal, intracavity, intraorbital, intraarticular, and transurethral, ​​as well as local delivery via a catheter or stent.

[0154] The method described herein can be used to treat a number of disorders related to chronic pain and central sensitization.These disorders include, for example, fibromyalgia, rheumatoid arthritis, osteoarthritis, chronic arthropathy, spinal nerve compression syndromes related to tumors and / or herniated disks, chronic back pain, chronic joint pain, trigeminal neuralgia, chronic metabolic neuropathy related to chronic pain, migraine, inflammatory pain, post-operative pain syndromes including phantom limb pain, post-traumatic stress disorder, irritable bowel syndrome, autonomic neuropathy, arachnoiditis, chronic localized pain syndromes, vulvodynia, and chronic pain syndromes related to the activation of central sensitization pathways.

[0155] Pharmaceutical compositions containing therapeutic small molecules according to the present disclosure may be formulated in any pharma- ceutically acceptable carrier or excipient. As used herein, the term "pharmaceutical acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Pharmaceutical compositions may include suitable solid or gel phase carriers or excipients. Exemplary carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Examples of pharma- ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In many cases, it will be preferable to include an isotonic agent in the composition, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.

[0156] Therapeutic small molecules may be incorporated into pharmaceutical compositions suitable for parenteral administration. Suitable buffers include, but are not limited to, sodium succinate, sodium citrate, sodium phosphate, or potassium phosphate. Sodium chloride may be used to modify the toxicity of the solution at a concentration of 0-300 mM (optimally 150 mM for liquid dosage forms). Cryoprotectants may include primarily 0-10% sucrose (optimally 0.5-1.0%) for lyophilized dosage forms. Other suitable cryoprotectants include trehalose and lactose. Bulking agents may include primarily 1-10% mannitol (optimally 2-4%) for lyophilized dosage forms. Stabilizers may be used in both liquid and lyophilized dosage forms, primarily 1-50 mM L-methionine (optimally 5-10 mM). Other suitable bulking agents include glycine, arginine, and may be included as 0-0.05% or less polysorbate 80 (optimally 0.005-0.01%). Additional surfactants include, but are not limited to, polysorbate 20 and BRIJ surfactants.

[0157] Therapeutic small molecule formulations may be lyophilized, preferably under reduced pressure, and stored as a sterile powder, and then reconstituted with bacteriostatic water (e.g., containing a benzyl alcohol preservative) or sterile water prior to injection. Pharmaceutical compositions may be formulated for parenteral administration by injection, e.g., bolus injection, or infusion.

[0158] Therapeutic small molecules may be administered once or multiple times as a preventative measure (i.e., to avoid disease). Alternatively, therapeutic small molecules may be administered to the patient at one time or over a series of treatments as appropriate, and may be administered to the patient at any time following diagnosis. Therapeutic small molecules may be administered as a monotherapy or in conjunction with other drugs or therapies useful in treating the condition.

[0159] Certain embodiments of the present invention are described herein, including the best mode for carrying out the invention known to the inventors. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that those skilled in the art will adopt such modifications as necessary, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by this application unless otherwise indicated herein or otherwise clearly contradicted by context.

[0160] Grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting the invention. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification shall be deemed to include the group as modified and thus satisfying the recitation requirements of all Markush groups used in the appended claims.

[0161] Administration Pharmaceutical compositions containing therapeutic molecules according to the present disclosure may be formulated in any pharma- ceutically acceptable carrier or excipient. As used herein, the term "pharmaceutically acceptable carrier" includes all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The pharmaceutical composition may include a suitable solid or gel phase carrier or excipient. Exemplary carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Examples of pharma- ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof. In many cases, it will be preferable to include an isotonic agent in the composition, e.g., sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances that enhance the shelf life or effectiveness of the therapeutic agent, e.g., wetting or emulsifying agents, preservatives, or buffers.

[0162] The therapeutic agent in the pharmaceutical composition may be formulated in a "therapeutically effective amount" or a "prophylactically effective amount". A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. The therapeutically effective amount may vary depending on the condition being treated, the severity and course of the condition, the method of administration, whether the agent is administered for prophylactic or therapeutic purposes, the bioavailability of the particular agent, the ability of the therapeutic small molecule to induce the desired response in the individual, previous treatments, the age, weight, and sex of the patient, the patient's clinical history and response to the agent, the type of therapeutic small molecule used, the discretion of the attending physician, and the like. A therapeutically effective amount is also an amount in which any toxic or harmful effects are outweighed by therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

[0163] The solution containing SOMAHOL (or other therapeutic molecules disclosed herein) is suitably administered to the patient at one time or over a series of treatments, and may be administered to the patient at any time from diagnosis onward. Alternatively, it may be administered as a preventative measure (i.e., to avoid the disease). The solution may be administered as a monotherapy or in conjunction with other drugs or therapies useful in treating the condition.

[0164] As a general proposition, a therapeutically or prophylactically effective amount of the therapeutic molecules disclosed herein, whether administered in one or multiple doses, is in the range of about 1 ng / kg body weight to about 100 mg / kg body weight. In certain embodiments, each therapeutic small molecule is administered in a range of about 1 ng / kg body weight to about 10 mg / kg body weight, about 1 ng / kg body weight to about 1 mg / kg body weight, about 1 ng / kg body weight to about 100 g / kg body weight, about 1 ng / kg body weight to about 10 g / kg body weight, about 1 ng / kg body weight / day to about 1 g / kg body weight, about 1 ng / kg body weight to about 100 ng / kg body weight, about 1 ng / kg body weight to about 10 ng / kg body weight, about 10 ng / kg body weight to about 100 mg / kg body weight, about 10 ng / kg body weight to about 1 ... g / kg body weight, approx. 10ng / kg body weight ~ approx. 1 mg / kg body weight, approx. 10 ng / kg body weight / ~ approx. 100 g / kg body weight, approx. 10 ng / kg body weight ~ approx. 10 mg / kg body weight, approx. 10 ng / kg body weight ~ approx. Body weight ~ approx. 100 ng / kg body weight / , approx. 100 ng / kg body weight ~ approx. 100 mg / kg body weight, approx. 100 ng / kg body weight ~ approx. 10 mg / kg body weight, approx. 100 ng / kg body weight ~ approx. 1 mg / kg body weight, approx. mg / kg body weight, about 100 ng / kg body weight to about 10 mg / kg body weight, about 100 ng / kg body weight to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight / day, about 1 m g / kg body weight ~ approx. 1 mg / kg body weight, approx. 1 mg / kg body weight ~ approx. 100 mg / kg body weight, approx. 1 mg / kg body weight ~ approx. 10 mg / kg body weight, approx. 10 mg / kg body weight ~ approx. 100 mg / kg body weight, approx. 10 mg / kg body weight ~ approx. 10 mg / k g body weight, about 10 mg / kg body weight to about 1 mg / kg body weight / day, about 10 mg / kg body weight to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 10 mg / kg body weight, about 100 mg / kg body weight / day to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 100 mg / kg body weight / day.

[0165] In some embodiments, the therapeutic molecules disclosed herein are administered in an amount of from about 10 ng to about 100 ng per individual administration, from about 10 ng to about 1 g per individual administration, from about 10 ng to about 10 g per individual administration, from about 10 ng to about 100 mg per individual administration, from about 10 ng to about 1 mg per individual administration, from about 10 ng to about 10 mg per individual administration, from about 10 ng to about 100 mg per individual administration, from about 10 ng to about 1000 mg per injection, from about 10 ng to about 10,000 mg per individual administration, from about 100 ng to about 1 mg per individual administration, from about 100 ng per individual administration, to about 10 mg, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 100 mg per injection, about 100 ng to about 1000 mg per individual administration, about 100 ng to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 10 00mg, about 1mg to about 10,000mg per individual administration, about 10mg to about 100mg per individual administration, about 10mg to about 1mg per individual administration, about 10mg to about 10mg per individual administration, about 10mg to about 100mg per individual administration, about 10mg to about 100mg per injection, about 10mg to about 10,000mg per individual administration, about 100mg to about 1mg per individual administration, about 100mg to about 100mg per individual administration, about 100mg to about 100mg per injection, about 10mg to about 10 Therapeutic small molecules are administered in the range of about 100 mg to about 10,000 mg, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1000 mg per injection, about 100 mg to about 10,000 mg per individual administration, and about 1000 mg to about 10,000 mg per individual administration. Therapeutic small molecules may be administered daily, every 2, 3, 4, 5, 6, 7, or 10 days, or every 1, 2, 3, or 4 weeks.

[0166] In other specific embodiments, the amount of therapeutic molecule disclosed herein may be administered in a dose of about 0.0006 mg, 0.001 mg, 0.003 mg, 0.006 mg, 0.01 mg, 0.03 mg, 0.06 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1 mg, 3 mg, 6 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 2000 mg, 5000 mg, or 10,000 mg. As expected, the dosage will depend on the condition, size, age, and condition of the patient.

[0167] In other aspects of this embodiment, the pharmaceutical composition compounds disclosed herein reduce signs / symptoms of a disease, such as a neurological disorder, by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein provide for the treatment of signs / symptoms of a disease, such as a neurological disorder, by, for example, about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, or , about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0168] The pharmaceutical composition disclosed herein is sufficient to allow individual regular administration.In some aspects of this embodiment, the pharmaceutical composition disclosed herein can be, for example, at least 5mg, at least 10mg, at least 15mg, at least 20mg, at least 25mg, at least 30mg, at least 35mg, at least 40mg, at least 45mg, at least 50mg, at least 55mg, at least 60mg, at least 65mg, at least 70mg, at least 75mg, at least 80mg, at least 85mg, at least 90mg, at least 95mg, or at least 100mg pharmaceutical composition. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein can be, for example, at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a pharmaceutical composition. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein may be in the range of, for example, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg.In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein may be administered in an amount of, for example, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg The amount of the active ingredient may be in the range of about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg.

[0169] The pharmaceutical compositions disclosed herein may include a solvent, emulsion, or other diluent in an amount sufficient to dissolve the pharmaceutical compositions disclosed herein. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may include a solvent, emulsion, or diluent in an amount of, for example, less than about 90% (v / v), less than about 80% (v / v), less than about 70% (v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), less than about 20% (v / v), less than about 15% (v / v), less than about 10% (v / v), less than about 5% (v / v), or less than about 1% (v / v). In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may contain a solvent, emulsion or other diluent in an amount, for example, from about 1% (v / v) to 90% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 40% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 80% (v / v), from about 1% (v / v) to 90% (v / v), from about 1% (v / v) to 100% (v / v), from about 1% (v / v) to 150% (v / v), from about 1% (v / v) to 20% (v / v), from about 1% (v / v) to 25% (v / v), from about 1% (v / v) to 30% (v / v), from about 1% (v / v) to 40% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 150% (v / v), from about 1% (v / v) to 25% (v / v), from about 1% (v / v) to 30% (v / v), from about 1% (v / v) to 40% (v / v), from about 1% (v / v) to 50% (v / v) ~ 30% (v / v), approximately 1% (v / v) ~ 20% (v / v), approximately 1% (v / v) ~ 10% (v / v), approximately 2% (v / v) ~ 50% (v / v), approximately 2% (v / v) )~40%(v / v), approx. 2%(v / v)~30%(v / v), approx. 2%(v / v)~20%(v / v), approx. 2%(v / v)~10%(v / v), approx. 4%(v / v)~ 50%(v / v), approx. 4%(v / v)~40%(v / v), approx. 4%(v / v)~30%(v / v), approx. 4%(v / v)~20%(v / v), approx. 4%(v / v)~1 0%(v / v), approx. 6%(v / v)~50%(v / v), approx. 6%(v / v)~40%(v / v), approx. 6%(v / v)~30%(v / v), approx. 6%(v / v)~20 % (v / v), about 6% (v / v) to 10% (v / v), about 8% (v / v) to 50% (v / v), about 8% (v / v) to 40% (v / v), about 8% (v / v) to 30% (v / v), about 8% (v / v) to 20% (v / v), about 8% (v / v) to 15% (v / v), or about 8% (v / v) to 12% (v / v).

[0170] The final concentration of the pharmaceutical composition disclosed herein in the pharmaceutical composition disclosed herein can be any desired concentration.In one aspect of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition can be a therapeutically effective amount.In another aspect of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition can be, for example, at least 0.00001mg / mL, at least 0.0001mg / mL, at least 0.001mg / mL, at least 0.01mg / mL, at least 0.1mg / mL, at least 1mg / mL, at least 10mg / mL, at least 25mg / mL, at least 50mg / mL, at least 100mg / mL, at least 200mg / mL, at least 500mg / mL. In other aspects of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition is, for example, about 0.00001 mg / mL to about 3,000 mg / mL, about 0.0001 mg / mL to about 3,000 mg / mL, about 0.01 mg / mL to about 3,000 mg / mL, about 0.1mg / mL to approx. 3,000mg / mL, approx. 1mg / mL to approx. 3,000mg / mL, approx. 250mg / mL to approx. 3,000mg / mL, approx. 500mg / mL to approx. 3,000mg / mL, approx. 750mg / mL to approx. 3,000mg / mL, approx. 1,000m g / mL ~ approx. 3,000 mg / mL, approx. 100 mg / mL ~ approx. 2,000 mg / mL, approx. 250 mg / mL ~ approx. 2,000 mg / mL, approx. 500 mg / mL ~ approx. 2,000 mg / mL, approx. 750 mg / mL ~ approx. 2,000 mg / mL, approx. 1,000 m g / mL~about 2,000mg / mL, about 100mg / mL~about 1,500mg / mL, about 250mg / mL~about 1,500mg / mL, about 500mg / mL~about 1,500mg / mL, about 750mg / mL~about 1,500mg / mL, about 1,000m g / mL ~ approx. 1,500 mg / mL, approx. 100 mg / mL ~ approx. 1,200 mg / mL, approx. 250 mg / mL ~ approx. 1,200 mg / mL, approx. 500 mg / mL ~ approx. 1,200 mg / mL, approx. 750 mg / mL ~ approx. 1,200 mg / mL, approx. 1,000 m g / mL~about 1,200mg / mL, about 100mg / mL~about 1,000mg / mL, about 250mg / mL~about 1,000mg / mL, about 500mg / mL~about 1,000mg / mL, about 750mg / mL~about 1,000mg / mL, about 100mg / mL mL ~ approx. 750 mg / mL, approx. 250 mg / mL ~ approx. 750 mg / mL, approx. 500 mg / mL ~ approx. 750 mg / mL, approx. 100 mg / mL ~ approx. 500 mg / mL, approx. 250 mg / mL ~ approx. 500 mg / mL, approx. 0.00001 mg / mL ~ approx. 0.00 The concentration may be in the range of about 0.01 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / mL to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about 100 mg / mL.

[0171] Some embodiments herein disclose, in part, treating individuals susceptible to or suffering from a disease (e.g., neurological disorder) or addiction. As used herein, the term "treatment" refers to reducing or removing signs / symptoms of a disease; or eliminating signs / symptoms. For example, the term "treat" can refer to reducing symptoms of a condition characterized by a disease, for example, by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. Those skilled in the art will understand the specific symptoms or indicators associated with a particular type of disease and will know how to determine whether an individual can be a candidate for the treatment disclosed herein.

[0172] In some aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of a disease by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of a disease by, for example, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a sign / symptom of a disease by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0173] In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein typically ranges from about 0.001 mg / kg to about 100 mg / kg, e.g., administered every 3, 5, 7, 10, or 14 days. In some aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be, e.g., at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1.0 mg / kg, at least 5.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, or at least 50 mg / kg, administered, e.g., every 3, 5, 7, 10, or 14 days. In other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein can be in the range of, for example, about 0.001 mg / kg to about 10 mg / kg, about 0.001 mg / kg / day to about 15 mg / kg, about 0.001 mg / kg to about 20 mg / kg, about 0.001 mg / kg to about 25 mg / kg, about 0.001 mg / kg to about 30 mg / kg, about 0.001 mg / kg to about 35 mg / kg, about 0.001 mg / kg to about 40 mg / kg, about 0.001 mg / kg to about 45 mg / kg, about 0.001 mg / kg to about 50 mg / kg, about 0.001 mg / kg to about 75 mg / kg, or about 0.001 mg / kg to about 100 mg / kg, and can be administered, for example, every 3, 5, 7, 10, or 14 days. In yet another aspect of this embodiment, an effective amount of a pharmaceutical composition disclosed herein is in the range of, for example, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 35 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.01 mg / kg to about 45 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 75 mg / kg, or about 0.01 mg / kg to about 100 mg / kg, and may be administered, for example, every 3 days, or every 5, 7, 10, or 14 days.In yet another aspect of this embodiment, an effective amount of a pharmaceutical composition disclosed herein is in the range of about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 35 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to about 45 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 75 mg / kg, or about 0.1 mg / kg to about 100 mg / kg, and may be administered, for example, every 3, 5, 7, 10, or 14 days.

[0174] The dosage may be a single dose or a cumulative dose (sequential administration), and can be easily determined by one skilled in the art. For example, the treatment of a disease or poisoning infection may include only one administration of an effective amount of the pharmaceutical composition disclosed herein. Alternatively, the treatment of a disease or poisoning may include multiple administrations of an effective amount of the pharmaceutical composition administered over a range of time periods, such as once a day, twice a day, three times a day, once every few days, or once a week. The timing of administration may vary from individual to individual, depending on factors such as the severity of the individual's symptoms. For example, an effective amount of the pharmaceutical composition disclosed herein may be administered to an individual once a day for an indeterminate period of time, or until the individual no longer requires treatment. One skilled in the art will know that an individual's condition will be monitored throughout the course of treatment, and that the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

[0175] In one embodiment, a therapeutic agent disclosed herein can reduce signs / symptoms of a disease, such as a neuropathy, by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% compared to a patient not receiving the same therapeutic agent. In other aspects of this embodiment, signs / symptoms of a disease, such as a neuropathy, are reduced or prevented by, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 100%, or about 15% relative to a patient not receiving the same therapeutic agent. reduced by about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0176] In further embodiments, the therapeutic small molecules and derivatives thereof have a half-life of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months or more.

[0177] In certain embodiments, the duration of administration of a therapeutic molecule disclosed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, administration is suspended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0178] In some aspects of this embodiment, a therapeutically effective amount of a therapeutic agent disclosed herein reduces signs / symptoms of a disease, such as a neuropathy, by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a therapeutic agent disclosed herein reduces signs / symptoms of a disease, such as a neuropathy, by, for example, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In still other aspects of this embodiment, the therapeutically effective amounts disclosed herein reduce signs / symptoms of a disease, such as a neuropathy, by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0179] In certain embodiments, treatment with a therapeutic molecule disclosed herein shortens recovery time from a disease, such as a neurological disorder, by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0180] In certain embodiments, treatment with a therapeutic molecule disclosed herein reduces signs / symptoms of addiction, such as withdrawal symptoms, by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0181] In certain embodiments, treatment with a therapeutic molecule disclosed herein enhances neuroplasticity and / or improves neurological function in, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50% of patients.

[0182] In one embodiment, the dose of the composition may be administered daily, twice weekly, weekly, biweekly, or monthly. The duration of treatment may be for one week, two weeks, one month, two months, four months, six months, eight months, one year, or more. The initial dose may be greater than the maintenance dose. In one embodiment, the dose is in the range of at least 0.01 mg / kg, at least 0.25 mg / kg, at least 0.3 mg / kg, at least 0.5 mg / kg, at least 0.75 mg / kg, at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 4 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 7 mg / kg, at least 8 mg / kg, at least 9 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, or at least 30 mg / kg weekly dose. In one embodiment, the weekly dose may be up to 1.5 mg / kg, up to 2 mg / kg, up to 2.5 mg / kg, up to 3 mg / kg, up to 4 mg / kg, up to 5 mg / kg, up to 6 mg / kg, up to 7 mg / kg, up to 8 mg / kg, up to 9 mg / kg, up to 10 mg / kg, up to 15 mg / kg, up to 20 mg / kg, up to 25 mg / kg, or up to 30 mg / kg. In certain aspects, the weekly dose may range from 5 mg / kg to 20 mg / kg. In alternative aspects, the weekly dose may range from 10 mg / kg to 15 mg / kg.

[0183] The present specification also provides pharmaceutical compositions for administering to subjects.The pharmaceutical compositions disclosed herein can further comprise pharma- ceutically acceptable carriers, excipients, or diluents.As used herein, the term "pharmaceutical acceptable" means that the composition is sufficient to achieve therapeutic effect without harmful side effects, and can be easily determined according to the type of disease, the age, weight, health condition, sex, and drug sensitivity of the patient, the route of administration, the mode of administration, the frequency of administration, the duration of treatment, the drugs used in combination or simultaneously with the compositions disclosed herein, and other factors known in medicine.

[0184] The pharmaceutical composition herein may further comprise a pharma- ceutically acceptable carrier.For oral administration, the carrier may comprise, but is not limited to, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a coloring agent, and / or a flavoring agent.For injectable formulations, the carrier may comprise a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, and a stabilizer.For topical formulations, the carrier may comprise a base, an excipient, a lubricant, and a preservative.

[0185] The disclosed compositions can be combined with the above-mentioned pharmaceutically acceptable carrier and formulated into various dosage forms.For example, for oral administration, pharmaceutical compositions can be formulated into tablets, lozenges, capsules, elixirs, suspensions, syrups or wafers.For injectable formulations, pharmaceutical compositions can be formulated into ampoules or multi-dose containers as single-dose forms.Pharmaceutical compositions can also be formulated into solutions, suspensions, tablets, pills, capsules, and long-acting formulations.

[0186] On the other hand, examples of carriers, excipients and diluents suitable for pharmaceutical preparations include, but are not limited to, lactose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.In addition, pharmaceutical preparations may further include fillers, anticoagulants, lubricants, humectants, flavorings and preservatives.

[0187] Furthermore, the pharmaceutical compositions disclosed herein may have the form of any formulation selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral liquids, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized formulations, and suppositories.

[0188] The compositions are formulated into a unitary dosage form suitable for the patient's body, preferably formulated into formulations useful for small molecule drugs by methods typical in the pharmaceutical art to be administered by oral, parenteral routes, such as, but not limited to, via dermal, intravenous, intramuscular, intraarterial, intramedullary, intraspinal, intraventricular, pulmonary, inhalation, transdermal, subcutaneous, intraperitoneal, intranasal, intracolonic, topical, sublingual, vaginal, or rectal administration.

[0189] The composition can be used by mixing with various pharma- ceutically acceptable carriers, such as physiological saline or organic solvents.To increase stability or absorbance, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers can be used.

[0190] The dosage and frequency of administration of the pharmaceutical compositions disclosed herein will be determined by the type of active ingredient, as well as by various factors such as the disease being treated, the route of administration, the age, sex, and weight of the patient, and the severity of the disease.

[0191] The total effective dosage of the compositions disclosed herein may be administered to a patient in a single dose or may be administered over an extended period of time in multiple doses according to a split treatment protocol. In the pharmaceutical compositions disclosed herein, the content of the active ingredient may vary depending on the severity of the disease. Preferably, the total daily dosage of the small molecules disclosed herein may be from about 0.0001 μg to about 500 mg / kg of patient body weight. However, the effective amount of the small molecule is determined by taking into consideration various factors including the age, body weight, health condition, sex, disease severity, diet, and secretion rate of the patient, in addition to the route of administration of the pharmaceutical composition and the frequency of treatment. Taking this into consideration, a person skilled in the art can easily determine an effective amount suitable for a particular use of the pharmaceutical compositions disclosed herein. The pharmaceutical compositions disclosed herein are not particularly limited in formulation, and in route and mode of administration, so long as they show suitable effects.

[0192] In addition, the pharmaceutical compositions may be administered alone or in combination with, or simultaneously with, other pharmaceutical agents that exhibit prophylactic or therapeutic efficacy.

[0193] In various embodiments, the formulations may include, but are not limited to, a combination of bioactive agents (such as viruses, proteins, antibodies, peptides, etc., as described herein) in the formulation. For example, the formulations described herein may include a single bioactive agent to treat one or more conditions, including but not limited to, a disease. The formulations disclosed herein may also include, in certain embodiments, two or more different bioactive agents for single or multiple conditions, including but not limited to, the use of multiple bioactive agents in the formulations may, for example, be directed to the same or different indications. Similarly, in another embodiment, multiple bioactive agents in the formulations may be used, for example, to treat both a pathological condition and one or more side effects caused by a primary treatment. In further embodiments, multiple bioactive agents may also be included in the formulations described herein to achieve different medical objectives, including, but not limited to, for example, simultaneously treating a pathological condition and monitoring the progression of a pathological condition. In additional embodiments, multiple, simultaneous therapies, such as those exemplified herein, as well as other combinations known in the art, are particularly useful for patient compliance, since a single composition may be sufficient for some or all of the suggested treatments and / or diagnoses. Those skilled in the art will know which bioactive agents can be mixed for a wide range of combination therapies.Similarly, in various embodiments, formulations can be used with small molecules and with combinations of one or more bioactive agents in addition to one or more small molecule pharmaceuticals.Thus, in various embodiments, formulations are provided that include 1, 2, 3, 4, 5, or 6 or more different bioactive agents, as well as one or more bioactive agents in combination with one or more small molecule pharmaceuticals.

[0194] In various embodiments, the formulation may include one or more preservatives and / or additives known in the art. Similarly, the formulation may be further formulated into various known delivery formulations, including, but not limited to, in certain embodiments. For example, in certain embodiments, the formulation may include surfactants, adjuvants, biodegradable polymers, hydrogels, and the like, and any such components, their chemical and functional properties are known in the art. Also known in the art are formulations that promote rapid, sustained or delayed release of bioactive agents after administration. The formulations described may be manufactured to include these or other formulation components known in the art.

[0195] The composition may thus be administered via an implantation device or catheter over time or as a continuous infusion, as a single dose or as two or more doses (which may or may not contain the same amount of the desired molecule). Further refinement of the appropriate dosage is routinely performed by, and is within the scope of work routinely performed by, those of skill in the art. The appropriate dosage may be confirmed by the use of appropriate dose-response data. In various embodiments, the bioactive agent in the formulations described herein may be administered to a patient over an extended period of time, such as, but not limited to, chronic administration for chronic conditions. The composition may be a solid, semi-solid, or aerosol, and the pharmaceutical composition is formulated as a tablet, gel tab, lozenge, orally dissolving strip, capsule, syrup, oral suspension, emulsion, granule, sprinkle, or pellet.

[0196] In some embodiments, for oral, rectal, vaginal, parenteral, pulmonary, sublingual, and / or intranasal delivery formulations, tablets may be prepared by compression or molding, optionally with one or more auxiliary ingredients or additives.In some embodiments, compressed tablets are prepared, for example, by compressing the active ingredient in a free-flowing form, such as powder or granules, mixed with a binder (e.g., but not limited to, povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., but not limited to, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), and / or surfactant or dispersant in a suitable tableting machine.

[0197] In some embodiments, molded tablets are made by, for example, but not limited to, molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable tablet press. In some embodiments, tablets can be optionally coated or scored, and formulated to provide slow and controlled release of active ingredients, for example, but not limited to, using hydroxypropylmethylcellulose in various ratios to provide a desired release profile. In some embodiments, tablets can be optionally coated, such as, but not limited to, a thin film, a sucrose coating, or an enteric coating, to provide release in parts of the intestine other than the stomach. In some embodiments, the processes, equipment, and contract manufacturers for tablet and capsule manufacturing are well known in the art.

[0198] In some embodiments, the capsule formulation can utilize hard or soft capsules, including, but not limited to, gelatin capsules or vegetable capsules, such as those made from hydroxymethylpropylcellulose (HMPC). In some embodiments, the type of capsule is a gelatin capsule. In some embodiments, the capsule can be filled using a capsule filler, such as, but not limited to, those available from commercial vendors, such as Miranda International, or by employing capsule manufacturing techniques well known in the industry, such as those described in detail in Pharmaceutical Capules, 2.sup.nd Ed., F.Podczeck and B.Jones, 2004. In some embodiments, the capsule formulation can be made using a contract manufacturing center, such as, but not limited to, the Chao Center for Industrial Pharmacy & Contract Manufacturing, located at Purdue Research Park.

[0199] The packaging and devices for administration may be determined by a variety of considerations, including, but not limited to, the volume of material to be administered, storage conditions, whether administration is by a skilled health practitioner or patient self-compliance, the administration schedule, the geopolitical environment (e.g., exposure to extreme temperature conditions in the case of developing countries), and other practical considerations.

[0200] Injection devices include pen-type injectors, autoinjectors, safety syringes, infusion pumps, jet pumps, infusion pumps, pre-filled glass syringes, pre-filled plastic syringes, and needleless syringes can be liquid-filled or dual-chambered, for example, for use with lyophilized materials. An example of a syringe for such use is the Lyo-Ject™ dual-chamber pre-filled syringe available from Vetter GmbH, Ravensburg, Germany. Another example is the LyoTip, a pre-filled syringe designed to conveniently deliver lyophilized formulations available from LyoTip, Inc., Camarillo, California, USA. Administration by injection can be, but is not limited to, intravenous, intramuscular, intraperitoneal, or subcutaneous, as appropriate. Administration by non-injection route can be, but is not limited to, nasal, oral, ocular, transdermal, or pulmonary, as appropriate.

[0201] In certain embodiments, the kit may include one or more single-chamber or multi-chamber syringes (e.g., liquid syringes and lyosyringes) for administering one or more formulations described herein. In various embodiments, the kit may include formulation components for parenteral, subcutaneous, intramuscular or IV administration, sealed in a vial under partial vacuum, ready for loading into a syringe and administration to a subject. In this case, the composition may be placed therein under partial vacuum. In all these and other embodiments, the kit may include one or more vials according to any of the above, each vial containing a single unit dose for administration to a subject.

[0202] The kit may include a lyophilisate, arranged as described herein, which upon reconstitution provides the composition accordingly, hi various embodiments, the kit may include a lyophilisate and a sterile diluent for reconstituting the lyophilisate.

[0203] Also described herein is a method for treating a subject in need of treatment, comprising administering to the subject an effective amount of the formulation disclosed herein. The therapeutically effective amount or dosage of the formulation depends on the disease or condition of the subject and the actual clinical setting.

[0204] In certain embodiments, the formulations described herein may be administered by any suitable route, particularly parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. It will also be understood that the preferred route will vary according to the condition and age of the recipient and the disease being treated. Methods for determining the most effective administration means and amounts are known to those skilled in the art and will vary according to, but not limited to, the composition used in the treatment, the purpose of the treatment, and the subject being treated. Single or multiple administrations may be performed, and the level and pattern of administration will be selected by, but not limited to, the treating physician. Suitable dosage formulations and methods of administering drugs are known in the art.

[0205] The formulations described herein can be used for the manufacture of drugs and for the treatment of humans and other animals by administration in accordance with conventional procedures.

[0206] Also provided herein are combinatorial approaches to develop suitable virus formulations using combinations of amino acids. These methods are effective for developing stable liquid or lyophilized pharmaceutical compositions, and in particular pharmaceutical virus formulations.

[0207] Compositions according to embodiments described herein have desirable properties, such as desirable solubility, viscosity, syringeability and stability. Lyophilizates according to embodiments described herein also have desirable properties, such as desirable recovery, stability and syringeability and reconstitution.

[0208] In some embodiments, the pH of the pharmaceutical formulation is at least about 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, or 9.

[0209] In one embodiment, the pH of the pharmaceutical formulation is about 3 to about 9, about 4 to about 19, about 5 to about 9, about 6 to about 8, about 6 to about 7, about 6 to about 9, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 7 to about 8, about 7 to about 9, or about 7 to about 10.

[0210] Working Example The following non-limiting examples are provided for illustrative purposes only, to facilitate a more complete understanding of the representative embodiments currently contemplated.These examples are intended to be only a small part of all possible situations in which the components of the formulation are combined.Therefore, these examples should not be interpreted as limiting any of the embodiments described herein, including those related to the type and amount of the components of the formulation, and / or the method and use.

[0211] Example 1 Rodent Models for the Assessment of PTSD Recent studies have shown that rodent models can simulate stress induction and disorder development. See, for example, Verbitsky et al. Translational Psychiatry (2020) 10:132. Physical stressors used to develop PTSD models include electric shock, underwater trauma, restraint / immobilization stress, and single prolonged stress. By manipulating stress type, intensity, duration, and frequency, preclinical models reflect the core PTSD phenotype, as measured by a variety of behavioral tests. There are two drugs indicated for the treatment of PTSD: sertraline and paroxetine.

[0212] In this example, rats are exposed to various stresses (e.g., electric shock, restraint / immobilization stress, and underwater trauma). The rats are then treated with Somahol and tested for signs / symptoms of PTSD. The treated rat population is compared to a control group.

[0213] The results showed that rats treated with Somahol (or other therapeutic molecules disclosed herein) recovered from PTSD more rapidly than the control group.

[0214] Example 2 Rodent Models for the Assessment of Addiction Two fundamental features of drug addiction in humans (i.e., loss of control over use and the resulting excessive or compulsive use of the drug) have been modeled in animals using several different methods. A convenient way to assess acquisition is to provide animals with access to the drug during daily experimental sessions, with delivery being available contingent on an operant response (i.e., lever pressing). Thus, this example relates to an effective animal model for studying addiction. Recent studies have shown that rodent models can simulate substance abuse and addiction. See, for example, Linch et al. Comparative Medicine (2010) Vol. 60, No. 3.

[0215] Rats are subjected to a rodent intravenous drug self-administration paradigm. Specifically, rats are implanted with a chronic indwelling catheter in the jugular vein. The catheter exits the rat dorsally, where it is connected to a tether-and-tubing system attached to a drug-filled syringe. Responses on an active lever result in infusion of drug.

[0216] Acquisition of drug self-administration is then measured as the number of sessions required to reach a criterion level of intake, which can be standardized and adjusted for dosage and drug availability. The ratio of active lever press responses to non-active lever press responses is used along with the intake criterion. All test animals are included in the analysis, regardless of whether they have acquired self-administration, and the focus is on how rapidly acquisition of self-administration occurs and the proportion of animals in each group that acquire drug self-administration.

[0217] As described above, rats are exposed to an opioid drug. Two populations of rats are exposed: the first population is then treated with Somahol, and the second population (i.e., control) is left untreated or injected with saline. The treated population of rats is compared to the control group. Specifically, the ratio of active lever pressing responses to non-active lever pressing responses is compared between the populations. The results show a lower ratio of lever pressing responses in rats treated with Somahol. The results suggest that Somahol (or other therapeutic molecules disclosed herein) prevents addiction and / or aids in recovery from addiction.

[0218] Example 3 Animal models for TBI The following examples relate to animal models that are effective for testing traumatic brain injury (TBI). Recent studies have shown that rodent models can simulate substance abuse and addiction. See, for example, Xiong et al. Nat Rev Neurosci. 2013 February; 14(2): 128-142. doi: 10.1038 / nrn3407. Animal TBI models include: Fluid percussion injury model Controlled cortical impact injury model Penetrating ballistic-like brain injury model Weight drop TBI model Models of blast TBI Mild TBI model

[0219] In this example, a fluid percussion model (FPI) is used to test the effect of Somahol on rats after FPI. In the FPI model, injury is inflicted by pendulum-driven piston strikes on reservoir fluid to generate fluid pressure pulses to intact dura through a craniotomy, either at the center or around the midline. In rats, LFPI produces a combination of focal cortical contusion and diffuse subcortical (such as hippocampus and thalamus) neuronal damage that occurs within minutes of impact, progresses to neuronal loss by 12 hours, and does not significantly extend to other brain regions until 7 days after injury. The contusion cortex below the injury site expands over several weeks into a glia-lined cavity that continues to expand for up to one year after injury due to progressive cell death. Over days to months, a progressive degenerative cascade persists in selectively vulnerable brain regions, including the ipsilateral hippocampus, thalamus, medial septum, striatum, and amygdala. LFPI produces neurobehavioural and cognitive deficits, including motor and memory impairments, commonly seen in patients with TBI. Cognitive and neurological deficits persist for more than one year after severe LFPI.

[0220] This approach produces characteristics of acute and chronic TBI similar to those observed in the LFPI literature, quantified by histologic and structural changes seen on MRI and chronic behavioral sequelae.

[0221] In this example, rats are subjected to pendulum blows. The rats are then treated with Somahol and examined for signs / symptoms of TBI. The treated population of rats is compared to a control group. The results show that rats treated with Somahol (or other therapeutic molecules disclosed herein) recover from TBI more rapidly than the control group.

[0222] Example 4 Animal Models for Multiple Sclerosis The following examples relate to effective animal models for testing multiple sclerosis (MS). The three best-characterized MS animal models are (1) experimental autoimmune / allergic encephalomyelitis (EAE); (2) a virus-induced chronic demyelinating disease known as Theiler's murine encephalomyelitis virus (TMEV) infection, and (3) toxin-induced demyelination. EAE is a model that better reflects the autoimmune pathogenesis of MS and is useful for testing potential experimental therapeutics. MS is a chronic immune-mediated inflammatory disease of the CNS (see, e.g., Frohman et al., 2006). The best-tested animal model of MS is experimental autoimmune encephalomyelitis (EAE), in which autoimmunity against CNS components is induced in susceptible mice via immunization with autoantigens derived from basic myelin proteins.

[0223] In this example, EAE is induced via active immunization with proteins or peptides or by passive transfer of encephalitogenic T cells. In both cases, the relevant immunogen is derived from a self-CNS protein such as myelin basic protein (MBP), proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG). Immunization of SJL / J mice with the immunodominant epitope of PLP (PLP139-151) induces a relapsing-remitting (RR) disease course (see, e.g., Tuohy et al., 1989), whereas disease induced by the immunodominant MOG35-55 peptide in C57Bl6 / J mice is of a chronic nature.

[0224] In this example, rats are the subjects and EAE is induced in two rat populations. The first population is also treated with Somahol (or other therapeutic molecules disclosed herein), and the second population (i.e., control) is left untreated or injected with saline. The treated rat population is compared to the control group with respect to MS signs / symptoms (e.g., inflammation). The results demonstrated that rats treated with Somahol exhibited less severe MS signs / symptoms. This suggests that Somahol (or other therapeutic molecules disclosed herein) confers resistance to autoimmune and related disorders.

[0225] Example 5 5-HT2A Human Serotonin GPCR Cell-Based Agonist Restin Assay This example was carried out to evaluate the potency (EC50) and efficacy (maximal response) of compounds against the human 5-HT2A receptor in stably transfected U2OS cells as determined by a GPCR cell-based assay.

[0226] Initially, cells were seeded in a total volume of 20 μL in white-walled 384-well microplates and incubated overnight at 37° C. before testing. For agonist measurements, cells were incubated with samples to induce a response. Intermediate dilutions of sample stocks were made to generate 5x samples in assay buffer. 5 μL of 5x samples were added to cells and incubated at 37° C. for 120 minutes. Final assay vehicle concentration was 1%. Results are expressed as percent efficacy relative to the maximum response of the control ligand. Assay volume was 20 μl in 384-well plates. Compounds were added in 5 μl of 5x compound, and were diluted 100x in solvent if originally in DMSO. Assays were performed such that the maximum allowed DMSO concentration was 1%. Assays were performed at 37° C. for 120 minutes. The reference agonist was serotonin.

[0227] The results are shown in Figure 11. The amino acid sequence of the 5-HT2A receptor external protein is SEQ ID NO:1: Amino acid sequence (extracellular portion 1-75, 133-148, 216-233, 347-362 -> PDZ domain 469-471 -> agonism is also shown in 155-160, 336-340) 10 20 30 MDILCEENTS LSSTTNSLMQ LNDDTRLYSN 40 50 60 DFNSGEANTS DAFNWTVDSE NRTNLSCEGC 70 80 90 LSPSCLSLLH LQEKNWSALL TAVVIILTIA 100 110 120 GNILVIMAVS LEKKLQNATN YFLMSLAIAD 130 140 150 MLLGFLVMPV SMLTILYGYR WPLPSKLCAV 160 170 180 WIYLDVLFST ASIMHLCAIS LDRYVAIQNP 190 200 210 IHHSRFNSRT KAFLKIIAVW TISVGISMPI 220 230 240 PVFGLQDDSK VFKEGSCLLA DDNFVLIGSF 250 260 270 VSFFIPLTIM VITYFLTIKS LQKEATLCVS 280 290 300 DLGTRAKLAS FSFLPQSSLS SEKLFQRSIH 310 320 330 REPGSYTGRR TMQSISNEQK ACKVLGIVFF 340 350 360 LFVVMWCPFF ITNIMAVICK ESCNEDVIGA 370 380 390 LLNVFVWIGY LSSAVNPLVY TLFNKTYRSA 400 410 420 FSRYIQCQYK ENKKPLQLIL VNTIPALAYK 430 440 450 SSQLQMGQKK NSKQDAKTTD NDCSMVALGK 460 470 QHSEEASKDN SDGVNEKVSC V

[0228] Example 6 5-HT6 Human Serotonin GPCR Cell-Based Agonist Restin Assay This example was carried out to evaluate the potency (EC50) and efficacy (maximal response) of compounds against the human 5-HT6 receptor in stably transfected DLD1 cells as determined by a GPCR cell-based assay.

[0229] Initially, cells were seeded in a total volume of 20 μL in white-walled 384-well microplates and incubated overnight at 37° C. before testing. For agonist measurements, cells were incubated with samples to induce a response. Intermediate dilutions of sample stocks were made to generate 5x samples in assay buffer. 5 μL of 5x samples were added to cells and incubated at 37° C. for 120 minutes. Final assay vehicle concentration was 1%. Results are expressed as percent efficacy relative to the maximum response of the control ligand. Assay volume was 20 μl in 384-well plates. Compounds were added in 5 μl of 5x compound, and were diluted 100x in solvent if originally in DMSO. Assays were performed such that the maximum allowed DMSO concentration was 1%. Assays were performed at 37° C. for 120 minutes. The reference agonist was serotonin / 5-HT. Results are shown in FIG. 12.

[0230] Example 7 TRKB human RTK kinase cell-based agonist functional assay This example was performed to evaluate the potency (EC50) and efficacy (maximal response) of compounds against human TrkB receptors in stably transfected U2OS cells as determined by the PathHunter receptor tyrosine kinase (RTK) cell-based assay.

[0231] Initially, cells were seeded in a total volume of 20 μL in white-walled 384-well microplates and incubated overnight at 37° C. before testing. For agonist measurements, cells were incubated with samples to induce a response. Intermediate dilutions of sample stocks were made to generate 5x samples in assay buffer. 5 μL of 5x samples were added to cells and incubated at 37° C. for 120 minutes. Final assay vehicle concentration was 1%. Results are expressed as percent efficacy relative to the maximum response of the control ligand. Assay volume was 20 μl in 384-well plates. Compounds were added in 5 μl of 5x compound, and were diluted 100x in solvent if originally in DMSO. Assays were performed such that the maximum allowed DMSO concentration was 1%. Assays were performed at room temperature for 180 minutes. The reference agonist was BDNF. Results are shown in FIG. 13.

[0232] Example 8 5-HT7 Human Serotonin GPCR Cell-Based Agonist cAMP Assay This example was performed to evaluate the potency (EC50) and efficacy (maximal response) of compounds against the human 5-HT7 receptor in stably transfected DLD1 cells as determined by a GPCR cell-based cAMP assay.

[0233] Initially, cells were seeded in a total volume of 15 μL in white-walled 384-well microplates and incubated overnight at 37° C. before testing. Prior to measurements, cell seeding medium was replaced with 15 μL of assay buffer (HBSS+10 mM HEPES). Briefly, intermediate dilutions of sample stocks were made to generate 4x samples in assay buffer. 5 μL of 4x samples were added to cells and incubated for 30 min at 37° C. The final assay vehicle concentration was 1%. Results are expressed as percent efficacy relative to the maximum response of the control ligand.

[0234] The assay volume was 20 μl in a 384-well plate. Compounds were added in 5 μl of 4x compound volume, and were diluted 100x in solvent if originally in DMSO. The assay was performed such that the maximum allowable DMSO concentration was 1%. The assay was performed at 37° C. for 30 minutes. The reference agonist was serotonin / 5-HT.

[0235] The results are shown in Figure 14. The amino acid sequence of the 5-HT7 receptor external protein is SEQ ID NO:2: Amino acid sequence (extracellular portion 1-83, 139-157, 223-236, 347-367 -> possible PDZ domains at or between all extracellular sites): 10 20 30 MMDVNSSGRP DLYGHLRSFL LPEVGRGLPD 40 50 60 LSPDGGADPV AGSWAPHLLS EVTASPAPTW 70 80 90 DAPPDNASGC GEQINYGRVE KVVIGSILTL 100 110 120 ITLLTIAGNC LVVISVCFVK KLRQPSNYLI 130 140 150 VSLALADLSV AVAVMPFVSV TDLIGGKWIF 160 170 180 GHFFCNVFIA MDVMCCTASI MTLCVISIDR 190 200 210 YLGITRPLTY PVRQNGKCMA KMILSVWLLS 220 230 240 ASITLPPLFG WAQNVNDDKV CLISQDFGYT 250 260 270 IYSTAVAFYI PMSVMLFMYY QIYKAARKSA 280 290 300 AKHKFPGFPR VEPDSVIALN GIVKLQKEVE 310 320 330 ECANLSRLLK HERKNISIFK REQKAATTLG 340 350 360 IIVGAFTVCW LPFFLLSTAR PFICGTSCSC 370 380 390 IPLWVERTFL WLGYANSLIN PFIYAFFNRD 400 410 420 LRTTYRSLLQ CQYRNINRKL SAAGMHEALK 430 440 450 LAERPERPEF VLRACTRRVL LRPEKRPPVS 460 470 VWVLQSPDHH NWLADKMLTT VEKKVMIHD

[0236] Example 9 5-HT2B Human Serotonin GPCR Cell-Based Agonist Calcium Flux Assay This example was carried out to evaluate the potency (EC50) and efficacy (maximal response) of compounds against the human 5-HT2B receptor in stably transfected HEK293 cells. The assay principle is a calcium mobilization-based assay.

[0237] First, cells were seeded in a white-walled 384-well microplate in a total volume of 20 μL and incubated overnight at 37° C. Prior to measurement, the cell seeding medium was replaced with 20 μL of dye loading solution (HBSS+20 mM HEPES containing 1× dye, 1× additive A and 2.5 mM probenecid). Plates were incubated at 37° C. for 45 min, followed by incubation at room temperature for 15 min.

[0238] 10 μl of assay buffer (HBS + 20 mM HEPES) was added to the cells. Intermediate dilutions of sample stocks were made to generate 4x samples in assay buffer. The assay plate, compound plate were loaded onto the FLIPR instrument. 10 μL of sample was added using the FLIPR on-board robot 5 seconds after calcium measurements were initiated. Final assay vehicle concentration was 1%. Results are expressed as percent efficacy relative to maximum response of control ligand.

[0239] The assay volume was 30 μl in a 384-well plate. Compounds were added in 10 μl of 4x compound volume, and if the compound was originally in DMSO, it was diluted 100x in solvent. The assay was performed such that the maximum allowable DMSO concentration was 1%. The assay was performed at 37° C., and the results were read as the compound was added. The reference agonist was serotonin.

[0240] The results are shown in Figure 15. The amino acid sequence of the 5-HT2A receptor external protein is SEQ ID NO:3: 5-HT2B receptor ectoprotein Amino acid sequence (extracellular portion 1-56, 114-129, 193-216, 346-360): 10 20 30 MALSYRVSEL QSTIPEHILQ STFVHVISSN 40 50 60 WSGLQTESIP EEMKQIVEEQ GNKLHWAALL 70 80 90 ILMVIIPTIG GNTLVILAVS LEKKLQYATN 100 110 120 YFLMSLAVAD LLVGLFVMPI ALLTIMFEAM 130 140 150 WPLPLVLCPA WLFLDVLFST ASIMHLCAIS 160 170 180 VDRYIAIKKP IQANQYNSRA TAFIKITVVW 190 200 210 LISIGIAIPV PIKGIETDVD NPNNITCVLT 220 230 240 KERFGDFMLF GSLAAFFTPL AIMIVTYFLT 250 260 270 IHALQKKAYL VKNKPPQRLT WLTVSTVFQR 280 290 300 DETPCSSPEK VAMLDGSRKD KALPNSGDET 310 320 330 LMRRTSTIGK KSVQTISNEQ RASKVLGIVF 340 350 360 FLFLLMWCPF FITNITLVLC DSCNQTTLQM 370 380 390 LLEIFVWIGY VSSGVNPLVY TLFNKTFRDA 400 410 420 FGRYITCNYR ATKSVKTLRK RSSKIYFRNP 430 440 450 MAENSKFFKK HGIRNGINPA MYQSPMRLRS 460 470 480 STIQSSSIIL LDTLLLTENE GDKTEEQVSY V

[0241] Example 10 Perturbed transcription assay The assay consisted of neurons tested in three stages: 1. baseline healthy cells, 2. cells perturbed with an anesthetic drug, 3. cells treated with therapeutic lead n, n+1, etc.

[0242] Plate N -Neurons are grown using standard stimulation procedures that include HGH -HGH treatment is discontinued and equilibrium is established - Take 100ug or 1 / 3 of the cells and mark the tube with a barcode -Put into RNA later solution, Store at -20°C. Stimulate the remaining cells with anesthetic for 48 hours at -37 °C. - Take 100ug or 1 / 2 of the remaining cells and mark the tube with a barcode -Put into RNA later solution, Store at -20°C. -Wash the cells Treat with therapeutic targets for 24 hours at -37°C incubation. -Harvest the remaining cells and mark the test tube with a barcode -Put into RNA later solution, Store at -20°C.

[0243] Control Plate -Neurons are grown using standard stimulation procedures that include HGH -HGH treatment is discontinued and equilibrium is established - Take 1 / 3 or 100ug of cells and mark the tube with a barcode -Put into RNA later solution, Store at -20°C.

[0244] Stimulate the remaining cells with anesthetic for 48 hours at 37℃ incubation. Then take 100ug or 1 / 2 of the cells at a minimum and mark the barcode in a test tube. Place in RNA later solution and store at -20℃. Next, wash the cells and incubate the cells at 37℃ for 24 hours. Take 100μg of cells, mark the barcode in a test tube, place in RNA later solution and store at -20℃.

[0245] Example 11 In silico structural screening of 5HT receptor binding candidates A scored set of 5HT receptor binding molecules is generated to evaluate AI output to guide synthetic approaches, including prodrug-like activity. The AI ​​scores are then compared with docking and activity to identify the most promising molecules for synthesis as prodrugs, fragments or full drug candidates.

[0246] AUTODOCK The goal of using Autodock is to generate relationships between compound activity and structure - which can then be used to design new drug candidates by evaluating these structures in silico. The quality of the in silico models can then be compared with Biacore assays and activity to understand the relationship between binding affinity and agonist / antagonist activity.

[0247] Screening may involve docking molecules into various 5H1 crystal structures to generate a range of numerical scores. Such structures may include both agonist and antagonist binding molecules of the same protein.

[0248] Primary targets are: -5-HT2A -5-HT2B -5-HT7 -TrkB.

[0249] FIG. 16 is a table of the results of the agonist assay from each molecule: A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3. Each molecule was tested at a concentration of 10 μM. As indicated, molecules were tested in each assay: arrestin, calcium flux, arrestin, cAMP, cell-based kinase. The targets were HTR2A, HTR2B, HTR6, HTR7D, and TrkB, respectively.

[0250] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on the embodiments described herein will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that those skilled in the art will adopt such modifications as necessary, and the inventors intend for the invention to be practiced in ways other than those specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is also encompassed by this application, unless otherwise indicated herein or otherwise clearly contradicted by the context.

[0251] Groupings of alternative embodiments, elements, or steps of the invention are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification will be deemed to be amended to include groups that thus satisfy the recitation requirements of all Markush groups used in the appended claims.

[0252] Unless otherwise indicated, all numbers expressing properties, items, amounts, parameters, properties, periods, etc. used in the specification and claims should be understood in all instances as being modified by the word "about". As used herein, the term "about" means that the property, item, amount, parameter, property, period so qualified encompasses a range of plus or minus 10% higher or lower than the value of the indicated property, item, amount, parameter, property, period. Thus, unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are approximations that may vary. To be conservative, and without any attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. Any numerical ranges and values, however, inherently contain certain errors necessarily resulting from the standard deviations found in their respective testing measurements. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and unless otherwise indicated herein, each separate value of a numerical range is incorporated into the specification as if it were individually set forth herein.

[0253] As used in the context of describing the present invention (particularly in the context of the following claims), the terms "a," "an," and "the" should be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to clarify the application and does not impose limitations on the scope of the application as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

[0254] Specific embodiments disclosed herein may be further limited in the claims using the language "consisting of" or "consisting essentially of." When used in the claims, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not expressly stated in the claim. The transitional term "consisting essentially of" limits the scope of the claim to those materials or steps expressly stated and those materials or steps that do not materially affect the underlying novel characteristics. Embodiments of the invention so claimed are essentially or explicitly described and enabled herein.

[0255] Groupings of alternative embodiments, elements, or steps of the invention should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or removed from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification will be deemed to be amended to include groups that thus satisfy the recitation requirements of all Markush groups used in the appended claims.

[0256] All patents, patent publications, and other publications mentioned or identified in this specification are individually and expressly incorporated herein by reference in their entirety, for example to describe and disclose the compositions and methods described in such publications and that can be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. Any dates or representations as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the accuracy of the dates or contents of these documents.

[0257] Finally, although aspects of the present specification are emphasized by referring to specific embodiments, it should be understood that those skilled in the art will readily recognize that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Thus, it should be understood that the disclosed subject matter is in no way limited to the specific methods, protocols, and / or reagents, etc. described herein. Thus, various modifications or alterations to the disclosed subject matter or alternative configurations of the disclosed subject matter may be made in accordance with the teachings of the specification without departing from the spirit of the specification. Finally, the terms used in the specification are for the purpose of describing specific embodiments only and are not intended to limit the scope of the present invention, which is defined solely by the claims. Thus, the present invention is not limited to what has been precisely shown and described.

[0258] Sequence Listing SEQ ID NO:1 (5-HT2A receptor external protein) MDILCEENTS LSSTTNSLMQ LNDDTRLYSN DFNSGEANTS DAFNWTVDSE NRTNLSCEGC LSPSCLSLLH LQEKNWSALL TAVVIILTIA GNILVIMAVS LEKKLQNATN YFLMSLAIAD MLLGFLVMPV SMLTILYGYR WPLPSKLCAV WIYLDVLFST ASIMHLCAIS LDRYVAIQNP IHHSRFNSRT KAFLKIIAVW TISVGISMPI PVFGLQDDSK VFKEGSCLLA DDNFVLIGSF VSFFIPLTIM VITYFLTIKS LQKEATLCVS DLGTRAKLAS FSFLPQSSLS SEKLFQRSIH REPGSYTGRR TMQSISNEQK ACKVLGIVFF LFVVMWCPFF ITNIMAVICK ESCNEDVIGA LLNVFVWIGY LSSAVNPLVY TLFNKTYRSA FSRYIQCQYK ENKKPLQLIL VNTIPALAYK SSQLQMGQKK NSKQDAKTTD NDCSMVALGK QHSEEASKDN SDGVNEKVSC V SEQ ID NO:2 (5-HT7 receptor ectoprotein) MMDVNSSGRP DLYGHLRSFL LPEVGRGLPD LSPDGGADPV AGSWAPHLLS EVTASPAPTW DAPPDNASGC GEQINYGRVE KVVIGSILTL ITLLTIAGNC LVVISVCFVK KLRQPSNYLI VSLALADLSV AVAVMPFVSV TDLIGGKWIF GHFFCNVFIA MDVMCCTASI MTLCVISIDR YLGITRPLTY PVRQNGKCMA KMILSVWLLS ASITLPPLFG WAQNVNDDKV CLISQDFGYT IYSTAVAFYI PMSVMLFMYY QIYKAARKSA AKHKFPGFPR VEPDSVIALN GIVKLQKEVE ECANLSRLLK HERKNISIFK REQKAATTLG IIVGAFTVCW LPFFLLSTAR PFICGTSCSC IPLWVERTFL WLGYANSLIN PFIYAFFNRD LRTTYRSLLQ CQYRNINRKL SAAGMHEALK LAERPERPEF VLRACTRRVL LRPEKRPPVS VWVLQSPDHH NWLADKMLTT VEKKVMIHD SEQ ID NO:3 (5-HT2B receptor ectoprotein) <h2 style=";text-align:left;direction:ltr">MALSYRVSEL QSTIPEHILQ STFVHVISSN<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> WSGLQTESIP EEMKQIVEEQ GNKLHWAALL<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ILMVIIPTIG GNTLVILAVS LEKKLQYATN<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> YFLMSLAVAD LLVGLFVMPI ALLTIMFEAM<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> WLPLVLCPA WLFLDVLFST ASIMHLCAIS<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> VDRYIAIKKP IQANQYNSRA TAFIKITVVW<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> LISIGIAIPV PIKGIETDVD NPNNITCVLT<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> KERFGDFMLF GSLAAFFTPL AIMIVTYFLT<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> IHALQKKAYL VKNKPPQRLT WLTVSTVFQR<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> DETPCSSPEK VAMLDGSRKD KALPNSGDET<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> LMRRTSTIGK KSVQTISNEQ RASKVLGIVF<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> FLFLLMWCPF FITNITLVLC DSCNQTTLQM<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> LLEIFVWIGY VSSGVNPLVY TLFNKTFRDA<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> FGRYITCNYR ATKSVKTLRK RSSKIYFRNP<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MAENSKFFKK HGIRNGINPA MYQSPMRLRS<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> STIQSSSIIL LDTLLLTENE GDKTEEQVSY

Claims

1. Compounds of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3 and E3, or analogs thereof: 【Chemistry 1】 【change】 【change】

2. A method of treating a disease comprising administering an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

3. 3. The method of claim 2, wherein the illness is one or more of anxiety, post-traumatic stress disorder (PTSD) and depression.

4. The method of claim 2, wherein the condition is a neurological disorder.

5. 5. The method of claim 4, wherein the neurological disorder is one or more of acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, epilepsy and seizures, Guillain-Barre syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headache, encephalitis, and myasthenia gravis.

6. The method of claim 2, wherein the effective amount is between 4 mg and 80 mg.

7. The method of claim 2, wherein the effective amount is between 4 mg and 1.2 g.

8. A method of enhancing neuroplasticity or improving neuronal function to treat a disease in a subject in need thereof, comprising administering a compound of formula I, or an analog thereof.

9. 9. The method of claim 8, wherein the disease is one or more of inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, epilepsy and seizures, Guillain-Barre syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headache, encephalitis, and myasthenia gravis.

10. A method of reversing the potent inhibition of dendritic branching comprising the administration of an effective amount of a compound of formula I, or an analog thereof.

11. 11. The method of claim 10, further comprising modulating expression of one or more of FOSB, CDC42 and ENTPD4.

12. 1. A method of ameliorating disorders of thiamine metabolism comprising administration of an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

13. 1. A method of increasing thiamine metabolism in the brain comprising administration of an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

14. A method of restoring neural excitation threshold comprising administration of an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

15. A method of treating a disease by lowering CCL2 levels comprising administering an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

16. The method of claim 15, wherein the condition is inflammation.

17. 16. A method of reducing inflammation comprising administration of an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

18. 16. A method of improving neurological function comprising administration of an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

19. A method of reversing inhibition of dendritic branching and / or improving neuronal metabolism comprising administration of an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

20. 1. A method of treating a neurological disorder, comprising the steps of: (a) identifying a patient having a neurological disorder; and (b) administering a therapeutic molecule to promote neuroplasticity, The method, wherein the therapeutic molecule is a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

21. 20. The method of claim 19, wherein the neurological disorder is one or more of acute spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, epilepsy and seizures, Guillain-Barre syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headache, encephalitis, and myasthenia gravis.

22. 16. A method of reducing amyloid plaques comprising administration of an effective amount of a compound of formula A1, B1, C1, D1, E1, F1, G1, H1, A2, B2, C2, D2, E2, F2, G2, H2, A3, B3, C3, D3, E3 or an analog thereof.

Images