Gapdh cascade inhibitor compounds and methods of use and treatment of stress induced disorders including mental illness

Abstract

The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siahl binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.

1 . A method for inhibition of the GAPDH-Siahl in the cells of a subject comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula I, 
       
         
           
           
               
               
           
         
       
       or formula II 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  can be the same or different, and can include H, OH, C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, C 2 -C 8  alkynyl, substituted C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, and C 2 -C 8  alkynyl, and a pharmaceutically acceptable carrier. 
       
     
     
         2 . A method for inhibition of p300 HAT and/or myocyte enhancer factor 2 (MEF) in the cells of a subject comprising administering to the subject a pharmaceutical composition comprising a compound of formula I, 
       
         
           
           
               
               
           
         
       
       or formula II 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  can be the same or different, and can include H, OH, C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, C 2 -C 8  alkynyl, substituted C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, and C 2 -C 8  alkynyl, and a pharmaceutically acceptable carrier. 
       
     
     
         3 . A method for inhibition of a stress induced disorder in an organ of a subject comprising administering to the subject a pharmaceutical composition comprising a compound of formula I, 
       
         
           
           
               
               
           
         
       
       or formula II 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  can be the same or different, and can include H, OH, C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, C 2 -C 8  alkynyl, substituted C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, and C 2 -C 8  alkynyl, and a pharmaceutically acceptable carrier. 
       
     
     
         4 . The method of  claim 3 , wherein the organ is the brain. 
     
     
         5 . The method of  claim 3 , wherein the stress induced disorder is selected from the group consisting of mood disorders, schizophrenia, autism and addictions. 
     
     
         6 . The method of  claim 3 , wherein the composition comprises at least one additional therapeutic composition. 
     
     
         7 . The method of  claim 6 , wherein the at least one additional therapeutic composition is selected from the group consisting of psychotropic agents, such as antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors, tricyclic antidepressants, anti-manics, anti-psychotics, phenothiazine antipsychotics, anxiolytics, sedatives, and hypnotics, barbiturate sedatives and hypnotics, benzodiazepine anxiolytics, sedatives, and hypnotics, and psychostimulants. 
     
     
         8 . The method of  claim 3 , wherein the organ is the heart. 
     
     
         9 . The method of  claim 8 , wherein the stress induced disorder is selected from the group consisting of cardiac hypertrophy or cardiomyopathy. 
     
     
         10 . The method of  claim 9 , wherein the composition comprises at least one additional therapeutic composition. 
     
     
         11 . The method of  claim 6 , wherein the at least one additional therapeutic composition is selected from the group consisting of α-blocker sympatholytics, sympatholytics, sympathomimetics, and adrenergic agonist sympathomimetics; cardiovascular agents, such as antianginals, antianginals, calcium-channel blocker antianginals, nitrate antianginals, antiarrhythmics, cardiac glycoside antiarrhythmics, class I antiarrhythmics, class antiarrhythmics, class antiarrhythmics, class IV antiarrhythmics, antihypertensive agents, α-blocker antihypertensives, angiotensin-converting enzyme inhibitor (ACE inhibitor) antihypertensives, β-blocker antihypertensives, calcium-channel blocker antihypertensives, central-acting adrenergic antihypertensives, diuretic antihypertensive agents, peripheral vasodilator antihypertensives, antilipemics, bile acid sequestrant antilipemics, reductase inhibitor antilipemics, inotropes, cardiac glycoside inotropes, thrombolytic agents, angiotensin II receptor blockers, digoxin, digitoxin, diuretics, and aldosterone antagonists. 
     
     
         12 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       ((1R,3R)-1,3-dimethyl-2-propargyl-1,2,3,4-tetrahydroisoquinoline); 
       
         
           
           
               
               
           
         
       
       ((1S,3S)-1,3-dimethyl-2-propargyl-1,2,3,4-tetrahydroisoquinoline); 
       
         
           
           
               
               
           
         
       
       ((R,S)-1-methyl-1,2,3,4-tetrahydroisoquinoline); 
       
         
           
           
               
               
           
         
       
       ((S)-1-methyl-1,2,3,4-tetrahydroisoquinoline); and 
       
         
           
           
               
               
           
         
       
       ((R)-1-methyl-propynyl-1,2,3,4-tetrahydroisoquinoline). 
     
     
         13 . The method of  claim 12 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       ((1R,3R)-1,3-dimethyl-2-propargyl-1,2,3,4-tetrahydroisoquinoline). 
     
     
         14 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  can be the same or different, and can include H, OH, C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, C 2 -C 8  alkynyl, substituted C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, and C 2 -C 8  alkynyl, with the proviso that R 1  to R 3  cannot each be H. 
       
     
     
         15 . The compound of  claim 14 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       ((1R,3R)-1,3-dimethyl-2-propargyl-1,2,3,4-tetrahydroisoquinoline). 
     
     
         16 . A compound of formula II: 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  can be the same or different, and can include H, OH, C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, C 2 -C 8  alkynyl, substituted C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, and C 2 -C 8  alkynyl, with the proviso that R 1  to R 3  cannot each be H. 
       
     
     
         17 . The compound of  claim 16 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       ((1S,3S)-1,3-dimethyl-2-propargyl-1,2,3,4-tetrahydroisoquinoline). 
     
     
         18 . A pharmaceutical composition comprising a compound of formula I, 
       
         
           
           
               
               
           
         
       
       or formula II 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  can be the same or different, and can include H, OH, C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, C 2 -C 8  alkynyl, substituted C 2 -C 8  alkyl, C 2 -C 8 , alkenyl, and C 2 -C 8  alkynyl, with the proviso that R 1  to R 3  cannot each be H, and a pharmaceutically acceptable carrier.