WO2025022402A1 - Compositions et méthodes de traitement de maladies comportementales - Google Patents

Compositions et méthodes de traitement de maladies comportementales Download PDF

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Publication number
WO2025022402A1
WO2025022402A1 PCT/IL2024/050740 IL2024050740W WO2025022402A1 WO 2025022402 A1 WO2025022402 A1 WO 2025022402A1 IL 2024050740 W IL2024050740 W IL 2024050740W WO 2025022402 A1 WO2025022402 A1 WO 2025022402A1
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alkyl
subject
optionally substituted
alkoxy
compound
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Inventor
Albert Pinhasov
Natalya Kogan
Igor KORMAN
Eyal Sharon
Tatiana ALKHAZOV
Dilorom BEGMATOVA
Liudmila VINNIKOVA
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Ariel Scientific Innovations Ltd
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Ariel Scientific Innovations Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/09—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton

Definitions

  • the present invention is in the field of, inter alia, docosatetraenoyl ethanolamide (DEA) derivatives, and use of same, such as for treatment of a behavior disease or disorder.
  • DEA docosatetraenoyl ethanolamide
  • Cannabinoid receptors and their endogenous agonists are found throughout the body and are involved in different physiological processes including inflammation pain, immune response, regulation of sleep and appetite.
  • the ECS is also important for learning and memory as well as for the regulation of emotional, motivational and cognitive functions and its modulation has shown to be protective against neurodegenerative disorders. Altered levels of endocannabinoids have been detected in neuropsychiatric disorders. It was suggested that the ECS could be used as a biomarker, and even as a potential target for the treatment of anxiety and depression. Accumulating evidences point to the role of ECS in borderline personality, antisocial behavior, post- traumatic stress disorder and manic-depressive disorder.
  • ECS is not only involved in psychiatric disorders, but also in normal emotional processing.
  • AEA and 2-Arachidonoylglycerol (2-AG) were shown to play a role in regulation of social behavior.
  • 2-AG 2-Arachidonoylglycerol
  • the present invention is based, at least in part on evaluation of endocannabinoid brain profiles in mouse social behavior models developed based on a selective breeding approach and food competition dominant-submissive relationship (DSR) test.
  • DSR food competition dominant-submissive relationship
  • the present invention in some embodiments, is based, at least in part on the findings that animals exhibit strong and stable characteristics of dominance or submissiveness, possess inherited stress resilience or vulnerability respectively and differentially respond to psychotropic agents.
  • their varied responses to a selected endocannabinoid were evaluated in an attempt to clarify the role of endocannabinoids in social dominance with potential ramifications on personality.
  • composition comprising the compound disclosed herein, and a pharmaceutically acceptable carrier.
  • a behavioral disease or disorder or ameliorating at least one symptom associated therewith in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound including any salt thereof, any enantiomer thereof, any cis/trans isomer thereof, any tautomer thereof, or a combination thereof, thereby treating a behavioral disease or disorder or ameliorating at least one symptom associated therewith in the subject, wherein the compound is represented by Formula 2: , wherein:
  • a method for determining suitability of a subject afflicted with a behavioral disease or disorder to treatment using a compound represented by Formula 2 comprising determining in a sample obtained or derived from the subject a level of DEA, wherein a level of DEA in the sample being greater than a predetermined threshold, is indicative of the subject being suitable for the treatment, thereby determining the suitability of the subject afflicted with a behavioral disease or disorder to treatment using the compound represented by Formula 2.
  • a method for diagnosing a subject with a behavioral disease comprising determining a level of an endocannabinoid in a sample obtained or derived from the subject, wherein the level of the endocannabinoid in the sample being greater than a predetermined threshold, is indicative of the subject being afflicted with or at increased risk of developing the behavioral disease, thereby, diagnosing the subject with a behavioral disease.
  • the C20-C30 alkenyl comprises between 2-6 unsaturated bonds.
  • the C20-C30 alkenyl comprises 4 unsaturated bonds.
  • the compound is selected from the group consisting of:
  • the pharmaceutical composition is for use in the treatment of a behavioral disease or disorder or amelioration of at least one symptom associated therewith, in a subject in need thereof.
  • the method further comprises a step after the determining, comprising administering to the subject determined as being suitable for the treatment a therapeutically effective amount of the compound represented by Formula 2 or a pharmaceutical composition comprising thereof.
  • the administering comprises a single administration, or multiple administrations.
  • the multiple administrations comprises daily administrations.
  • the treating or treatment comprises reducing or inhibiting nociception, anxiety, depression, or any combination thereof, in the subject.
  • the behavioral disease or disorder is selected from the group consisting of: a social behavior problem, anxiety, depression, a neurodegenerative disease, a personality disorder, and any combination thereof.
  • the subject is characterized by submissive behavior and/or p sy chopathology .
  • the functional analog comprises the compound disclosed herein.
  • the endocannabinoid comprises a compound being represented by Formula 2.
  • the endocannabinoid is DEA.
  • all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
  • Fig. 1 includes a chemical structure of docosatetraenoyl ethanolamide (DEA).
  • Figs. 2A-2B include vertical bar graphs showing whole brain levels of gene expression in submissive (Sub) and dominant (Dom) mice.
  • mRNA expression was measured by the real-time RT-PCR in whole brain extracts of Sub and Dom male mice. The data is presented as relative abundance. * - p ⁇ 0.05 by Mann- Whitney t-test.
  • Figs. 3A-3D include vertical bar graphs showing the effects of acute DEA treatment on thermal hyperalgesia induced by a hot plate in Sub and Dom mice.
  • Figs. 4A-4D include vertical bar graphs showing the effects of acute DEA (5, 10 and 15 mg/kg) treatment on locomotory activity in Elevated Plus-Maze (EPM) in Sub and Dom mice.
  • EPM Elevated Plus-Maze
  • Control 1:1:18 ethanokTween 80:saline. All the data are represented as mean ⁇ SEM.
  • Figs. 5A-5C include graphs showing the effects of DEA (5 mg/kg) treatment on animal behavior in Dominant-Submissive Relationship (DSR) test.
  • n 5 per group.
  • the duration of treatment lasted for 9 days.
  • Control 1:1:18 ethanokTween 80:saline. All the data are represented as mean ⁇ SEM.* p ⁇ 0.05 vs. control, by multiple t-test.
  • Figs. 6A-6D include vertical bar graphs showing the effects of acute DEA (5, 10 and 15 mg/kg) treatment on anxiolytic activity in Elevated Plus-Maze in Sub and Dom mice.
  • Figs. 7A-7E include vertical bar graphs showing whole brain levels of gene expression in Sub and Dom mice.
  • CB 1 Cannabinoid receptor type 1
  • CB2 Cannabinoid receptor type 2
  • 7C) G Protein-Coupled Receptor 55 GPR55
  • Gene expression was measured by real-time RT- PCR in whole brain extracts of Sub and Dom male mice. The data is presented as relative abundance.
  • the C20-C30 alkenyl comprises 2 or more (e.g. 2, 3, 4, 5, or 6 or between 3-6) unsaturated bonds. In some embodiments, the C20-C30 alkenyl comprises 4 double bonds (e.g. cis-double bonds). In some embodiments, R is a residue of docosatetraenoic acid or homogammalinolenic acid.
  • the compound of the invention is represented by Formula 1, wherein R is a residue of a naturally occurring fatty acid; and wherein R is devoid of a residue of arachidonic acid.
  • the compound represented by Formula 1 is selected from:
  • the compound comprises any salt, any enantiomer, any cis/trans isomer, any tautomer, or a combination thereof, of the compound represented by Formula 1.
  • a pharmaceutical composition comprising the compound of the invention, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound represented by Formula 1, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for use in the treatment of a behavioral disease or disorder or amelioration of at least one symptom associated therewith in a subject in need thereof.
  • the pharmaceutical composition comprising a compound represented by Formula 1, and a pharmaceutically acceptable carrier is for use in the treatment of a disease related to fatty acid desaturase 2 (FADs2), elongase of very-long fatty acid 5 (Elovl5), or both, in a subject in need thereof.
  • FADs2 fatty acid desaturase 2
  • Elovl5 very-long fatty acid 5
  • a pharmaceutical composition comprising a compound represented by Formula 2, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound represented by Formula 2, and a pharmaceutically acceptable carrier, for use in the treatment of a behavioral disease or disorder or amelioration of at least one symptom associated therewith in a subject in need thereof.
  • the pharmaceutical composition comprising a compound represented by Formula 2, and a pharmaceutically acceptable carrier is for use in the treatment of a disease related to FADs2, Elovl5, or both, in a subject in need thereof.
  • the pharmaceutical composition comprises an active agent and a pharmaceutically acceptable carrier, wherein the active carrier consists essentially of a compound represented by Formula 1 or Formula 2.
  • a pharmaceutical composition comprising an active agent and a pharmaceutically acceptable carrier, wherein the active carrier consists essentially of a DEA.
  • the term “consist or consisting essentially of’ denotes that a given compound or substance, e.g., the active agent constitutes the vast majority of the active ingredient's portion or fraction of the composition.
  • consists essentially of means that a compound represented by Formula 1 or Formula 2 constitutes at least 95%, at least 98%, at least 99%, or at least 99.9% by weight, of the active ingredient(s) of the composition, or any value and range therebetween.
  • a compound represented by Formula 1 or Formula 2 constitutes at least 95%, at least 98%, at least 99%, or at least 99.9% by weight, of the active ingredient(s) of the composition, or any value and range therebetween.
  • the pharmaceutical composition is for use in the treatment of a behavioral disease or disorder or amelioration of at least one symptom associated therewith, in a subject in need thereof.
  • the composition is formulated for: intraperitoneal administration, intravenous administration, transdermal administration, intramuscular administration, or any combination thereof.
  • carrier refers to any component of a pharmaceutical composition that is not the active agent.
  • pharmaceutically acceptable carrier refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline.
  • sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethy
  • substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate) as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations.
  • sugar, starch, cellulose and its derivatives powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier (
  • wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants, and preservatives may also be present.
  • Any non-toxic, inert, and effective carrier may be used to formulate the compositions contemplated herein.
  • Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J.
  • compositions examples include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO.
  • the presently described composition may also be contained in artificially created structures such as liposomes, ISCOMS, slow-releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides in serum.
  • Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • Liposomes for use with the presently described peptides are formed from standard vesicle-forming lipids which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally determined by considerations such as liposome size and stability in the blood.
  • the carrier may comprise, in total, from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions presented herein.
  • a pharmaceutically-acceptable carrier suitable for the preparation of unit dosage form of a composition as described herein for peroral administration is well-known in the art.
  • compositions further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.
  • binders e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone
  • disintegrating agents e.g. cornstarch, potato starch, alg
  • sodium lauryl sulfate permeation enhancers
  • solubilizing agents e.g., glycerol, polyethylene glycerol
  • stabilizers e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose
  • viscosity increasing agents e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g.
  • diethyl phthalate, triethyl citrate polymer coatings (e.g., poloxamers or poloxamines), and/or coating and film forming agents (e.g., ethyl cellulose, acrylates, poly methacrylates ) .
  • polymer coatings e.g., poloxamers or poloxamines
  • coating and film forming agents e.g., ethyl cellulose, acrylates, poly methacrylates
  • preparation of effective amount or dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models, and such information can be used to more accurately determine useful doses in humans.
  • toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals.
  • the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosages vary depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g., Fingl, et al., (1975) "The Pharmacological Basis of Therapeutics", Ch. 1 p.l].
  • a method for treating a behavioral disease or disorder or ameliorating at least one symptom associated therewith in a subject in need thereof is provided.
  • a disease related to FADs2 and “FADs2-related disease” are used herein interchangeably, and refer to any disease or disorder, including any symptom associated therewith, wherein a FADs2 gene or a protein encoded therefrom is involved, induces, initiates, propagates, determines, or any combination or equivalent thereof, in the pathogenesis, pathophysiology, or both.
  • a disease related to Elovl5 and “El ovl 5 -related disease” are used herein interchangeably, and refer to any disease or disorder, including any symptom associated therewith, wherein a Elovl5 gene or a protein encoded therefrom is involved, induces, initiates, propagates, determines, or any combination or equivalent thereof, in the pathogenesis, pathophysiology, or both.
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound including any salt thereof, any enantiomer thereof, any cis/trans isomer thereof, any tautomer thereof, or a combination thereof, thereby treating a behavioral disease or disorder or ameliorating at least one symptom associated therewith in the subject, wherein the compound is represented by Formula 2: , wherein:
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising docosatetraenoyl ethanolamide (DEA) or a functional analog thereof, thereby treating a behavioral disease or disorder or ameliorating at least one symptom associated therewith in the subject.
  • a pharmaceutical composition comprising docosatetraenoyl ethanolamide (DEA) or a functional analog thereof, thereby treating a behavioral disease or disorder or ameliorating at least one symptom associated therewith in the subject.
  • DEA docosatetraenoyl ethanolamide
  • the DEA or a functional analog thereof is represented by Formula 2.
  • a functional analog of DEA is represented by Formula 1.
  • Formula 1 does not include or excludes DEA.
  • a functional analog of DEA includes any compound having essentially similar activity of DEA as disclosed herein, e.g., anxiolytic, analgesic, antinociception, anti-depressive, or any combination thereof.
  • “essentially similar” comprises having at least 70% ,80%, 90%, 95%, or 99% the activity of DEA, or any value and range therebetween. Each possibility represents a separate embodiment of the invention.
  • a compound represented by Formula 1 or Formula 2 is characterized by anxiolytic activity , analgesic activity , anti-nociception activity , anti- depressive activity, or any combination thereof.
  • the subject is characterized by: (a) expression levels of: fatty acid desaturase 2 (FADs2), elongase of very-long fatty acid 5 (Elovl5), or both, being greater than in a healthy control; (b) expression levels of at least one cannabinoid system related gene selected from: cannabinoid receptor type 1 (CB1), cannabinoid receptor type 2 (CB2), transient receptor potential cation channel subfamily V member 1 (TRPV1), G protein- coupled receptor 55 (GPR55), G protein-coupled receptor 18 (GPR18), or any combination thereof, being essentially identical to a healthy control; or (c) both (a) and (b). [068] In some embodiments, the method further comprises a step comprising determining expression level of: FADs2, Elovl5, or both, in a sample obtained or derived from the subject.
  • FADs2 fatty acid desaturase 2
  • Elovl5 very-long fatty acid 5
  • determining is in vitro or ex vivo determining.
  • an expression level of any one of FADs2, Elovl5, or both in the sample (e.g., obtained or derived from the subject) being greater than or compared to a healthy control, is indicative of the subject being suitable for treatment according to the method of the invention.
  • an expression level of any one of FADs2, Elovl5, or both, in the sample (e.g., obtained or derived from the subject) being essentially similar or equivalent to a healthy control, is indicative of the subject being unsuitable for treatment according to the method of the invention.
  • “essentially similar or equivalent” refers to an expression level in the sample obtained or derived from the subject being at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the expression level in a healthy control, or any value and range therebetween. Each possibility represents a separate embodiment of the invention.
  • the method comprises determining in a sample obtained or derived from the subject an expression level of: FADs2, Elovl5, or both.
  • expression level of FADs2, Elovl5, or both, in the sample of the subject being greater compared to a healthy control is indicative of the subject being suitable for the treatment with the compound represented by Formula 2, thereby selecting a subject being suitable for treatment with the compound represented by Formula 2.
  • expression level of FADs2, Elovl5, or both, in the sample of the subject being equal, equivalent, essentially similar to a healthy control, is indicative of the subject being unsuitable for the treatment with the compound represented by Formula 2.
  • the method further comprises a step proceeding the determining comprising administering to the subject selected as being suitable for treatment with the compound represented by Formula 2, a therapeutically effective amount of a pharmaceutical composition comprising the compound represented by Formula 2.
  • the subject is afflicted with a behavioral disease or disorder.
  • the behavioral disease or disorder is selected from: anxiety, depression, a social behavior problem, a neurodegenerative disease, a personality disorder, a psychiatric and/or psychological disorder, or any combination thereof.
  • the subject is characterized by submissive behavior and/or psychopathology.
  • a social behavior problem is selected from: conduct disorder, oppositional defiant disorder (ODD), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), behavioral addition, or any combination thereof.
  • ODD oppositional defiant disorder
  • ADHD attention deficit hyperactivity disorder
  • OCD obsessive compulsive disorder
  • a risk for developing a behavior problem is selected from: childhood substance abuse, low self-esteem, parental substance abuse, lack of parental supervision as a childhood, traumatic events, exposure to toxic substances as a child, lack of emotional attachment to parents, associating with peers involved in deviant behavior, or any combination thereof.
  • the method comprises determining in a sample obtained or derived from the subject a level of DEA.
  • a level of DEA in the sample being greater than a predetermined threshold is indicative of the subject being suitable for the treatment.
  • a level of DEA in the sample being lower than or equal to a predetermined threshold is indicative of the subject being unsuitable for the treatment.
  • the sample comprises any biological sample obtained or derived from the subject.
  • the term “biological sample” refers to any type of physical specimen which has been obtained, collected, derived, dissected or any equivalent thereof, from a subject.
  • the biological sample comprises biological fluids selected from: serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, urine, cerebrospinal fluid, saliva, sputum, tears, perspiration, mucus, or tissue culture media, or any combination thereof.
  • the biological sample is selected from: tissue extracts, homogenized tissue, cellular extracts, or a biopsy, or any combination thereof.
  • the sample comprises a biopsy of a brain tissue of the subject.
  • the sample comprises a blood sample of the subject, including any processed blood derivative, such as, serum, plasma, etc.
  • the treatment comprises a treatment using the compound represented by Formula 2, according to the method of the invention.
  • the method further comprises a step comprising administering to a subject determined as being suitable for treatment a therapeutically effective amount of the compound represented by Formula 2 or a pharmaceutical composition comprising thereof.
  • the administering step is performed after the determining step.
  • the administering comprises a single administration. In some embodiments, the administering comprises multiple administrations.
  • multiple administrations comprises daily administrations.
  • the administering comprises: intraperitoneally administering, intravenously administering, transdermally administering, intramuscularly administering, or any combination thereof.
  • the treating comprises reducing or inhibiting nociception, anxiety, depression, or any combination thereof, in the subject.
  • EPM elevated plus maze
  • DSR dominant-submissive relationship test
  • Sub Dominant and Submissive murine model organism
  • the method comprises determining a level of an endocannabinoid in a sample obtained or derived from the subject.
  • a level of the endocannabinoid in the sample being greater than or equal to a predetermined threshold, is indicative of the subject being afflicted with or at increased risk of developing the behavioral disease, thereby, diagnosing the subject with a behavioral disease.
  • a level of the endocannabinoid in the sample being equal to or lower than a predetermined threshold, is indicative of the subject being afflicted with or at increased risk of developing the behavioral disease, thereby, diagnosing the subject with a behavioral disease.
  • a level of the endocannabinoid in the sample being greater than or equal to a predetermined threshold, is indicative of the subject being not afflicted with or at reduced risk of developing the behavioral disease.
  • a level of the endocannabinoid in the sample being equal to or lower than a predetermined threshold, is indicative of the subject being not afflicted with or at reduced risk of developing the behavioral disease.
  • the endocannabinoid comprises a compound being represented by Formula 2. In some embodiments, the endocannabinoid is DEA.
  • treatment encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder or condition is totally cured.
  • a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life.
  • treating comprises ameliorating.
  • reduce, reducing, inhibit, or inhibiting is at least 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction or inhibition compared to a control, or any value and range therebetween.
  • reduce, reducing, inhibit, or inhibiting is at least 5%, 10%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction or inhibition compared to a control, or any value and range therebetween.
  • increase, increasing, enhance, or enhancing is at least 5%, 10%, 35%, 50%, 80%, 100%, 150%, 270%, 400%, 650%, 800%, or 1,000% increase compared to a control, or any value and range therebetween.
  • increase, increasing, enhance, or enhancing is at least 5%, 10%, 35%, 50%, 80%, 100%, 150%, 270%, 400%, 650%, 800%, or 1,000% increase compared to a control, or any value and range therebetween.
  • reduce, reducing, inhibit, or inhibiting is 5-100%, 10-100%, 25-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, 95- 100%, or 97-100% reduction or inhibition compared to a control.
  • reduce, reducing, inhibit, or inhibiting is 5-100%, 10-100%, 25-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, 95- 100%, or 97-100% reduction or inhibition compared to a control.
  • increase, increasing, enhance, or enhancing is 5-100%, 10- 200%, 35-400%, 50-500%, 80-550%, 100-600%, 150-700%, 270-750%, 400-850%, 650- 900%, 800-1000%, or 1,000-1,200% increase compared to a control, or any value and range therebetween.
  • increase, increasing, enhance, or enhancing is 5-100%, 10- 200%, 35-400%, 50-500%, 80-550%, 100-600%, 150-700%, 270-750%, 400-850%, 650- 900%, 800-1000%, or 1,000-1,200% increase compared to a control, or any value and range therebetween.
  • Each possibility represents a separate embodiment of the invention.
  • increase, increased, reduce, or reduced is compared to a control.
  • the composition delivered in a controlled release system is formulated for intravenous infusion, implantable osmotic pump, transdermal patch, liposomes, or other modes of administration.
  • a pump is used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989).
  • further polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
  • the amount of a composition to be administered will be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the tubes were vortexed and then sonicated for 30 min in an ice-cold sonication bath (taken for a brief vortex every 10 min). Then, Ultra performance liquid chromatography (UPLC)-grade water: methanol (3:1, v/v) solution (0.5 ml) was added to the tubes followed by centrifugation. The upper organic phase was transferred, and the polar phase was reextracted as described above, with 0.5 ml of MTBE. Both organic phases were combined and dried in speedvac and then stored at -80 °C. For analysis, the dried lipid extracts were re-suspended in 100 pl mobile phase B (see below) and centrifuged again at 13,000 rpm at 4 °C for 10 min.
  • UPLC Ultra performance liquid chromatography
  • Chromatographic separation was performed on an ACQUITY UPLC BEH C8 column (2.1 x 100 mm, i.d., 1.7 pm) (Waters Corp., MA, USA).
  • the mobile phase A consisted of 45% water (UPLC grade) with 1% 1 M NH4Ac, 0.1% acetic acid, and with 55% acetonitrile: isopropanol (7:3) with 1% 1 M NH4Ac, 0.1% acetic acid (mobile phase B).
  • the column was maintained at 40 °C and the flow rate of the mobile phase was 0.4 mlxmin -1 .
  • Mobile phase A was run for 1 min at 100%, then gradually reduced to 25% at 12 min, following a decrease to 0% at 16 min.
  • Nitrogen was used as de-solvation and cone gas at a flow rate of 800 Ixh 1 and 30 Ixh -1 , respectively.
  • the mass spectrometer was operated in full scan HDMS E resolution mode over a mass range of 50-2000 Da.
  • a collision energy ramp of 20-80 eV was applied, for the low energy scan function - 4 eV was applied.
  • HMDB Human Metabolome Database
  • ChemSpider LipidBlast
  • IDTT Integrated DNA Technologies
  • the GAPDH gene was used as an endogenous control.
  • RT-PCRs were performed in an Azure ceilo system, using the Prime-Time qPCR Assay (IDT). Reaction mixes of 20 pl contained 3 pl of cDNA, 10 pl of 2 x master mix buffer, 1 pl of Prime-Time qPCR Probe assay (containing the primers and the probe), and 6 pl of water.
  • the amplification program was as follows: 95 °C for 3 minutes, 44 cycles of 95 °C for 10 s, and 60 °C for 30 s.
  • DEA was synthesized and purified as previously described Hanus et al., 1993.
  • DEA was administered intraperitoneally (5 mg/kg, 10 mg/kg or 15 mg/kg). One hour after the injection the animals were subjected to Elevated Plus Maze (EPM) test and Hot Plate test.
  • EPM Elevated Plus Maze
  • the hot plate test is employed to assess nociception and serves as a test for investigating the effects of analgesics.
  • the hot plate was pre-heated to 55° Celsius.
  • the animal was placed on the hot plate.
  • the animal is removed immediately after appearance of a nociceptive response such as hind paw licking, hind paw flicking, vocalization or jumping. If the mouse showed no such response within 15 seconds, it was removed from the apparatus to prevent tissue damage (Deuis et al., 2017).
  • DSR test is a repeated food competition paradigm leading to the formation of pairs representing dominant-submissive relationships.
  • DSR test was initially developed to study submissiveness as a model of depressive-like behavior and dominance as a model of manic- like behavior (Malatynska and Knapp, 2005; Malatynska et al., 2007).
  • DSR paradigm By employing DSR paradigm and based on breeding approach the inventors developed two mice populations that exhibit strong and stable characteristics of dominance and submissiveness (Feder et al., 2010) Nesher et al., 2015; Basil et al., 2018; Gross et al., 2018). DSR tests were carried out on nine consecutive days.
  • mice were deprived of food, but water was provided ad libitum. During a 5 min session milk drinking scores were recorded, and then the drinking time for each mouse manually counted by a human observer. DEA (5mg/kg) was injected i.p. 30 min before placing the pair of mice into DSR apparatus.
  • TripleQ targeted LC-MS lipidomic analysis of the brain samples revealed several differences between the ‘Dom’ and ‘Sub’ populations.
  • the levels of long-chain ethanolamides, specifically C20 (eicosa-) and C22 (docosa-), especially with 3 to 5 double bonds were found to be elevated in the ‘Sub’ group compared to the ‘Dom’ group (Table 2).
  • AEA (20:4), DTEA (22:3), EPEA (20:5) and DHEA (22:6) were significantly higher in male ‘Sub’ group compared to the respective ‘Dom’ group, while ETEA (20:3) was higher in female ‘Sub’ group.
  • DEA (22:4) levels were elevated in both males and females ‘Sub’ compared to respective ‘Dom’ groups. No significant difference among ‘Dom’ and ‘Sub’ mice in the content of monounsaturated DEEA (22:1), saturated DSEA (22:0), as well as medium-chained fatty acid ethanolamides were observed (Table 2).
  • DEA DEA-based on the endocannabinoid profiles observed, DEA, which was found as most significantly different between ‘Dom’ and ‘Sub’ male and female mice, was evaluated on animal responses in behavioral tests aimed to assess nociception (hot plate), anxiety (EPM) and social behavior (DSR).
  • the endocannabinoidome encompasses structural related lipid mediators (Di Marzo and Wang, 2014; Piscitelli, 2015) involved in diverse biochemical mechanisms, with broad modulatory effects extending beyond the traditional endocannabinoid signaling pathways (Pacher. 2006; Pacher and Kunos, 2013; Pacher et al., 2020).
  • TRPV1 vanilloid receptor 1
  • PUFAs a family of fatty acids that are a major component of endocannabinoids (Spector. 1999) are typically classified based on the number and position of their double carbon bonds.
  • AA the parent fatty acid of AEA and 2- AG
  • this family includes other fatty acids such as a-linolenic acid (ALA; 18:3), EPA (20:5), DHA (22:6), linoleic acid (LA; 18:2), DA (22:4), and others.
  • Dysregulation of PUFA homeostasis can worsen the course of mental illness and may serve as a trigger for neurodegenerative processes (Petermann et al., 2022; Stanchowicz, 2023).
  • PUFA supplementation was found to be partially favorable in anxiety, depression, attention- deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), dementia, mild cognitive impairment, Huntington's disease, and schizophrenia (Gao et al., 2022). It was also suggested that decreased circulating PUFAs were correlated with risk of ADHD, ASD, bipolar disorder, and schizophrenia (Gao et al., 2022). Several studies suggest that increased levels of PUFAs could alleviate symptoms or lower the risk of various mental disorders (Gao et al., 2022). Therefore, the inventors might infer that distinct behavioral characteristics of ‘Dom’ and ‘Sub’ mice may stem from different levels of specific PUFAs observed in their brains.
  • the concentrations of PUFA in the body are typically mirrored by the levels of their ethanolamide derivatives.
  • Supplementing milk formulae with AA and DHA raised the levels of the corresponding NAEs, AEA and DHEA, in certain brain regions in piglets (Banni and di Marzo, 2010).
  • feeding with an AA-rich diet exhibited increased AEA concentrations in the mice whole brain (Banni and di Marzo, 2010).
  • the inventors assume that the differences in the levels of the parental fatty acids (DA and EPA), in brains of ‘Dom’ and ‘Sub’ mice observed in untargeted lipidomic analysis (in agreement with differences of their appropriate ethanolamide derivatives in the targeted analysis) indicates that the regulation of endocannabinoid biosynthesis in these behaviorally distinct populations may occur upstream of the endpoint derivatives.
  • the current assumption was further confirmed by differential expression of genes encoding the enzymes (FADS2 and EL0VL5) responsible for PUFAs biosynthesis in the brain of Dom and Sub mice.
  • ELOVL5 can condense a wide selection of PUFAs, including linoleic acid to produce arachidonic acid, a-linolenic to produce eicosapentaenoic, and stearidonic acid to produce docosahexaenoic acid (Shikama et al., 2015). It is highly expressed in the central nervous system and mutations in the gene are the cause of spino-cerebellar ataxia type 38 (SC A38), a rare autosomal neurological disease characterized by gait abnormality, dysarthria, dysphagia, hyposmia and peripheral neuropathy (Balbo et al., 2021). While changes in ELOVL5 expression have been linked to prognosis in cancer patients (Kieu et al., 2022), its role in behavior regulation is still unclear.
  • SC A38 spino-cerebellar ataxia type 38
  • DEA was previously shown to produce classical cannabinoid-like effects at higher concentrations (15-60 mg/kg), lower doses were considered to be not active (Berg et al., 1995). Indeed, the inventors found that, among tested doses (5, 10, 15mg/kg) the significant antinociceptive effect was observed at a dose of 15 mg/kg, however only in Sub mice. While no anxiolytic effect was observed, 15 mg/kg induced mice locomotion. interesting, that this phenomenon was also examined only in Sub, but not in Dom mice. The dose of 5 mg/kg had no effect in either hot plate or EPM, in Sub or Dom mice.
  • Dom and Sub mice differentially respond to psychotropic agents (Nesher et al., 2013; Murlanova et al., 2021).
  • acute administration of selective serotonin reuptake inhibitor paroxetine produced pronounced antidepressant-like effect in Sub, while caused paradoxical (frenetic) activity in Dom (Nesher et al., 2013).
  • Differential responses were also observed with mood stabilizers and addictive compounds (Nesher et al., 2013; Murlanova et al., 2021).
  • the inventors suggest that the treatment with lower doses of DEA may exert modularity effect on social (hierarchy -based) personality.
  • social hierarchy is linked to personality traits in both animals and humans (Colleter and Brown, 2011; David et al., 2011; Dasgupta et al., 2022; Vekony et al., 2022).
  • dominant individuals tend to be more assertive, confident, and proactive (Blanchard et al., 1988; Salonen et al., 2022), while submissive individuals are often more anxious, passive, and reactive (Catarino et al., 2014; Zaffar and Arshad, 2020).
  • social hierarchy can shape an individual's behavior and physiology (Schmid Mast, 2010; Flota-Banuelos et al., 2019), including stress responses (Knight and Mehta, 2017; Karamihalev et al., 2020), brain activity (Breton et al., 2014; Williamson et al., 2019a), and gene expression (Pohorecky et al., 2004; Horii et al., 2017; Lea et al., 2018; Williamson et al., 2019b).
  • DEA As DEA is higher in Sub mice, it would be straightforward to assume that its administration may enhance submissiveness, but this oversimplification appears to be incorrect. DEA was not able to reduce submissiveness of selectively bred Sub animals. The inventors may suggest that elevation of DEA in the brain of Sub mice acts as a compensatory mechanism to counterbalance submissiveness-associated features including enhanced stress vulnerability, anxiety, and social deficits. This phenomenon should be further evaluated as it places the endocannabinoid system as an important factor in regulation of social behavior. It is possible that the DEA may act through activation of a signal transduction pathway, distinct from a canonical cannabinoid receptors -mediated neurotransmission.
  • This pathway is activated by DEA at levels that do not produce the classical CBl-mediated psychotropic and antinociceptive effects. It is partially supported by gene expression analysis of Sub vs Dom mice brain, which did not show any significant differences in the expression levels of cannabinoid system related genes, including CB 1, CB2, TRPV1, GPR55, and GPR18.
  • DEA was prepared from docosatetraenoic acid through fatty-acyl chloride step:
  • reaction mixture was stirred for 1 h, water (10 mL) was added, and the mixture was acidified to pH 3 with 1 N HC1.
  • the product was extracted with ether (3 x 50 mL) and dried (MgSO4), and solvent was evaporated under reduced pressure.
  • the crude material was chromatographed on silica gel (2-10% methanol in dichloromethane).

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Abstract

La présente invention concerne des composés, une composition les comprenant, et leurs procédés d'utilisation, tels que dans une méthode de traitement d'une maladie ou d'un trouble du comportement ou du soulagement d'au moins un symptôme associé à celui-ci chez un sujet en ayant besoin.
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