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(12) Patent Application Publication (10) Pub. No.: US 2017/0020892 A1 Thompson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0020892 A1 Thompson Et Al US 20170020892A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0020892 A1 Thompson et al. (43) Pub. Date: Jan. 26, 2017 (54) USE OF NEGATIVE MODULATORS OF Related U.S. Application Data GABA RECEPTORS CONTAINING ALPHAS SUBUNITS AS FAST ACTING (60) Provisional application No. 61/972,446, filed on Mar. ANTDEPRESSANTS 31, 2014. (71) Applicant: University of Maryland, Baltimore, Publication Classification Baltimore, MD (US) (51) Int. Cl. A 6LX 3/557 (2006.01) (72) Inventors: Scott Thompson, Baltimore, MD (US); A6II 3/53 (2006.01) Mark D. Kvarta, Ellicott City, MD A6II 45/06 (2006.01) (US); Adam Van Dyke, Baltimore, MD (52) U.S. Cl. (US) CPC ........... A61 K3I/55.17 (2013.01); A61K 45/06 (2013.01); A61 K3I/53 (2013.01) (73) Assignee: University of Maryland, Baltimore, Baltimore, MD (US) (57) ABSTRACT Embodiments of the disclosure include methods and com (21) Appl. No.: 15/300,984 positions related to treatment of one or more medical conditions with one or more negative modulators of GABA (22) PCT Filed: Mar. 31, 2015 receptors. In specific embodiments, depression and/or Sui cidability is treated or ameliorated or prevented with one or (86) PCT No.: PCT/US2O15/023667 more negative modulators of GABA receptors, such as a S 371 (c)(1), partial inverse agonist of a GABA receptor comprising an (2) Date: Sep. 30, 2016 alpha5 subunit. Patent Application Publication Jan. 26, 2017. Sheet 1 of 12 US 2017/002O892 A1 ×1/ /|\ Patent Application Publication Jan. 26, 2017. Sheet 3 of 12 US 2017/002O892 A1 & Patent Application Publication Jan. 26, 2017. Sheet 4 of 12 US 2017/002O892 A1 Patent Application Publication Jan. 26, 2017. Sheet 5 of 12 US 2017/002O892 A1 SuÐquunOOB‘NSnduueOOdd|H Patent Application Publication Jan. 26, 2017. Sheet 6 of 12 US 2017/002O892 A1 an O O L CO OO O O N Ha ?m 3LO (O - CD H -- o . CO : CD d O 8 as ? D O O O O O O O O Od OO N CO O s (e.O. 9%) eoueuegeld eSOJOnS 16 > s O O N- CO O CD H. : . ?h : (O : : H ? CO O O O O O O OO CO s CN O OO Ole uOOeuelu Patent Application Publication Jan. 26, 2017. Sheet 7 of 12 US 2017/002O892 A1 Patent Application Publication Jan. 26, 2017. Sheet 8 of 12 US 2017/002O892 A1 oC) O N OO h g S CO : C -CO LOr Q cpLO - CD -- H. : ce CD .C. as D -- OO C ofCD a 9) O C Cld 9 F L C23 9. C CS ? O O O O O c5 O O O OO N. CO O r : r H. : n- bO). CO %) eoueuegeld( eSOJOnS Patent Application Publication Jan. 26, 2017. Sheet 9 of 12 US 2017/002O892 A1 OOZ 00|| Ollel uOOeueueoOS eOueuepeud eSOJOnS 00||00|| O O eouelejeud eSOJOnS Patent Application Publication Jan. 26, 2017. Sheet 10 of 12 US 2017/002O892 A1 s Patent Application Publication Jan. 26, 2017. Sheet 11 of 12 US 2017/0020892 A1 c CN y oo co N. c. o CD ch r O O O O e eAeuel Oud peZeuON aa V V 9 Patent Application Publication Jan. 26, 2017. Sheet 12 of 12 US 2017/0020892 A1 O CD of) of) 9) C CD N D O CD CD D -- L CO D O CD . d5 of) (s ? O O O O O O 2 OO CO s CN euOZ uOOeuelu u eu 9% CD O CD 2 D O C CN g V N 9 :r . CD ? O O O OO euOZ uOOeuelu u eu 9% US 2017/002O892 A1 Jan. 26, 2017 USE OF NEGATIVE MODULATORS OF conditions. In particular embodiments, the one or more GABA RECEPTORS CONTAINING ALPHAS medical conditions includes depression and similar condi SUBUNITS AS FAST ACTING tions. The condition may be of any kind, but in specific ANTIDEPRESSANTS embodiments the condition being treated is major depression and/or Suicidality. In specific embodiments, treatment of the CROSS-REFERENCE TO RELATED medical condition occurs at a more rapid rate than currently APPLICATIONS known treatments and has fewer deleterious side effects. In specific embodiments, the medical condition is a depression 0001. This application claims priority to U.S. Provisional related disorder; an anxiety-related disorder, an attention Patent Application No. 61/972,446, filed on Mar. 31, 2014, related disorder; a psychosis-related disorder; an eating which is incorporated by reference herein in its entirety. disorder; a personality disorder, cognitive impairment, including that follows traumatic brain injury (TBI) or that is STATEMENT REGARDING FEDERALLY non-TBI cognitive impairment; neuropathic pain; chronic SPONSORED RESEARCH OR DEVELOPMENT muscle or bone pain; diabetic complications resulting in 0002 This invention was made with government support nerve injury; generalized attack of muscular weakness; under Grant Number MH086828 awarded by the National recurring sleep episodes during the day; migraine; addiction; Institutes of Health. The government has certain rights in the or a combination thereof. invention. 0008 Embodiments of the present disclosure relate to a method for treating or ameliorating depression and/or Sui TECHNICAL FIELD cidality in a human Subject comprising administering to the 0003 Embodiments of the disclosure are related at least subject a therapeutically effective amount of a modulator of to the fields of cell biology, molecular biology, biochemistry, a GABA receptor. Although any modulator of a GABA neurology, psychiatry, pharmacology, psychology, and receptor that ameliorates a medical condition as described medicine. In specific embodiments, the disclosure relates to herein, in a specific embodiment the modulator is a negative methods for treating or ameliorating depression and/or Sui modulator of the receptor. In specific embodiments, the cidality in a Subject by administering one or more modula modulator is a negative allosteric modulator of GABA tors of the GABA receptor that can produce a rapid anti receptors containing an alpha5 subunit. depressant action. 0009 Specific embodiments of the disclosure concern the use of negative allosteric modulators of alpha5 subunit BACKGROUND containing GABA receptors as fast-acting antidepressants to address depression and/or reduce Suicidality. In specific 0004. There is a need to identify new drugs that can be embodiments, fast-acting as used herein is defined as the used to treat depressive disorders and reduce the incidence onset of therapeutic effects being within hours to days of suicide on a worldwide basis. Selective serotonin compared to current therapies that take days to weeks to reuptake inhibitors (SSRIs) are often the first line of treat months. ment, but many patients do not respond to these medications 0010. In particular embodiments, any and all drugs that and prolonged treatment (several weeks or months) is often are negative allosteric modulators of alpha5 subunit-con required to achieve therapeutic improvement. taining GABA receptors (including inverse agonists at the 0005. The GABA receptor is an ionotropic receptor and benzodiazepine binding site of GABA receptors containing ligand gated ion channel. Its endogenous ligand is gamma alpha5 Subunits) will produce a rapid antidepressant action aminobutyric acid (GABA), the major inhibitory neurotrans and will produce a rapid decrease in depression and/or mitter in the central nervous system. The primary activation Suicidality in patients Suffering from major depression or in site of the GABA receptor is the binding site for GABA and patients suffering from depression that are not suicidal. several drugs, such as muscimol, gaboXadol, and bicucul Because alpha5-containing GABA receptors are narrowly line. A second binding site is the so-called “benzodiazepine expressed in the hippocampus and cortex, and because in at receptor’ site. Drugs binding at this site can promote or least some embodiments the Substances are weak inverse impair the ability of GABA to activate the GABA receptor. agonists, in certain embodiments they have a significantly GABA receptors occur in all organisms with a central greater therapeutic potential than current treatments. nervous system. Because of their wide distribution within 0011. In one embodiment the present disclosure relates to the nervous system of mammals, they play a role in virtually a method for treating or ameliorating depression and/or all brain functions. Suicidality in a human Subject comprising administering to 0006 Ketamine, a recognized antagonist of the NMDA the Subject a therapeutically effective amount of a negative type glutamate receptor, has demonstrated fast-acting anti allosteric modulator of the GABA receptor, and in some depressant properties. However, ketamine is recognized to embodiments the modulator is administered orally, intrad have potent psychotomimetic effects and the mechanism of ermally, intramuscularly, intraperitonealy, intravenously, via action of ketamine remains uncertain. Thus, there is a clear insufflation, or in a dermal patch. clinical need for the identification of other fast-acting anti 0012. The present disclosure relates to a method for depressants for depression and Suicidality that have treating or ameliorating depression and/or Suicidality in a enhanced pharmacokinetic properties and that can yield human Subject comprising administering to the Subject a more robust responses with less negative side effects. therapeutically effective amount of a negative allosteric BRIEF SUMMARY modulator of the alpha5 subunit of the GABA receptor and in some embodiments the modulator is administered orally 0007 Embodiments of the disclosure concern methods intradermally, intramuscularly, intraperitonealy, intrave and compositions for the treatment of one or more medical nously, via insufllation, or in a dermal patch. US 2017/002O892 A1 Jan. 26, 2017 0013. In another embodiment the present disclosure stimulants, anti-glucocorticoids, antagonists of NMDA-type relates to a method for treating or ameliorating depression glutamate receptors, tricylic antidepressants (TCAS), and and/or Suicidality in a human Subject comprising adminis combinations thereof. tering to the subject a therapeutically effective amount of 0019.
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