Methods and compositions for the treatment of neuropsychiatric disorders

Abstract

The present invention relates to methods and compositions for treating neuropathic pain and neuropsychiatric disorders by administering agents that are effective in reducing the effective amount, inactivating, and/or inhibiting the activity of a Na + —K + -2Cl − (NKCC) cotransporter. In certain embodiments, the Na + —K + -2Cl − co-transporter is NKCC1.

1 . A method for treating a neuropsychiatric disorder in a mammalian subject, comprising administering an effective amount of a composition comprising a Na + K + 2Cl co-transporter antagonist to the subject. 
     
     
         2 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist reduces or blocks hypersynchronized neuronal population discharges by non-synaptic effects. 
     
     
         3 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a NKCC1 co-transporter antagonist. 
     
     
         4 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a CNS-targeted NKCC co-transporter antagonist. 
     
     
         5 . The method of  claim 4 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: furosemide; bumetanide; ethacrynic acid; torsemide; azosemide; muzolimine; piretanide; hipamide; and functional analogs and derivatives thereof. 
     
     
         6 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: thiazide; and thiazide-like diuretics. 
     
     
         7 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein 
         R 1  is not present, H or O; 
         R 2  is H or when R 1  is O, is selected from the group consisting of: alkylaminodialkyl, alkylaminocarbonyldialkyl, alkyloxycarbonylalkyl, alkylaldehyde, alkylketonealkyl, alkylamide, an alkylammonium group, alkylcarboxylic acid, alkylheteroaryls, alkylhydroxy, a biocompatible polymer, methyloxyalkyl, methyloxyalkaryl, methylthioalkylalkyl and methylthioalkaryl, unsubstituted or substituted, and when R 1  is not present, R 2  is selected from the group consisting of hydrogen, dialkylamino, diarylamino, dialkylaminodialkyl, dialkylcarbonylaminodialkyl, dialkylesteralkyl, dialkylaldehyde, dialkylketonealkyl, dialkylamido, dialkylcarboxylic acid, and dialkylheteroaryls, unsubstituted or substituted; 
         R 3  is selected from the group consisting of: aryl, halo, hydroxy, alkoxy, and aryloxy, unsubstituted or substituted; and 
         R 4  and R 5  are each independently selected from the group consisting of: hydrogen, alkylaminodialkyl, alkylhydroxyaminodiakyl, unsubstituted or substituted. 
       
     
     
         8 . The method of  claim 7 , wherein the Na + K + 2Cl co-transporter antagonist, is selected from the group consisting of: bumetanide aldehyde; bumetanide dibenzylamide; bumetanide diethylamide; bumetanide morpholinoethyl ester; bumetanide 3-(dimethylaminopropyl)ester; bumetanide N,N-diethylglycolamide ester; bumetanide dimethylglycolamide ester; bumetanide pivaxetil ester; bumetanide benzyltrimethyl-ammonium salt; and bumetanide cetyltrimethylammonium salt. 
     
     
         9 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound of formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein 
         R 1  is not present, H or O; 
         R 2  is H or when R 1  is O, is selected from the group consisting of: alkylaminodialkyl, alkylaminocarbonyldialkyl, alkyloxycarbonylalkyl, alkylaldehyde, alkylketonealkyl, alkylamide, an alkylammonium group, alkylcarboxylic acid, alkylheteroaryls, alkylhydroxy, a biocompatible polymer, methyloxyalkyl, methyloxyalkaryl, methylthioalkylalkyl and methylthioalkaryl, unsubstituted or substituted, and when R 1  is not present, R 2  is selected from the group consisting of hydrogen, dialkylamino, diarylamino, dialkylaminodialkyl, dialkylcarbonylaminodialkyl, dialkylesteralkyl, dialkylaldehyde, dialkylketonealkyl, dialkylamido, dialkylcarboxylic acid, and dialkylheteroaryls, unsubstituted or substituted; 
         R 3  is selected from the group consisting of aryl, halo, hydroxy, alkoxy, and aryloxy, unsubstituted or substituted; and 
         R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkylaminodialkyl, alkylhydroxyaminodiakyl, unsubstituted or substituted; 
       
     
     
         10 . The method of  claim 9 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: furosemide aldehyde; furosemide ethyl ester; furosemide cyanomethyl ester; furosemide benzyl ester; furosemide morpholinoethyl ester; furosemide 3-(dimethylaminopropyl)ester; furosemide N,N-diethylglycolamide ester; furosemide dibenzylamide; furosemide benzyltrimethylammonium salt; furosemide cetyltrimethylammonium salt; furosemide N,N-dimethylglycolamide ester; furosemide pivaxetil ester; and furosemide propaxetil ester. 
     
     
         11 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound of formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein 
         R 1  is not present, H or O; 
         R 2  is H or when R 1  is O, is selected from the group consisting of: alkylaminodialkyl, alkylaminocarbonyldialkyl, alkyloxycarbonylalkyl, alkylaldehyde, alkylketonealkyl, alkylamide, an alkylammonium group, alkylcarboxylic acid, alkylheteroaryls, alkylhydroxy, a biocompatible polymer, methyloxyalkyl, methyloxyalkaryl, methylthioalkylalkyl and methylthioalkaryl, unsubstituted or substituted, and when R 1  is not present, R 2  is selected from the group consisting of: hydrogen, dialkylamino, diarylamino, dialkylaminodialkyl, dialkylcarbonylaminodialkyl, dialkylesteralkyl, dialkylaldehyde, dialkylketonealkyl, dialkylamido, dialkylcarboxylic acid, and dialkylheteroaryls, unsubstituted or substituted; 
         R 3  is selected from the group consisting of: aryl, halo, hydroxy, alkoxy, and aryloxy, unsubstituted or substituted; and 
         R 4  and R 5  are each independently selected from the group consisting of: hydrogen, alkylaminodialkyl, alkylhydroxyaminodiakyl, unsubstituted or substituted. 
       
     
     
         12 . The method of  claim 11 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: piretanide aldehyde; piretanide methyl ester; piretanide cyanomethyl ester; piretanide benzyl ester; piretanide morpholinoethyl ester; piretanide 3-(dimethylaminopropyl)ester; piretanide N,N-diethylglycolamide ester; piretanide diethylamide; piretanide dibenzylamide; piretanide benzyltrimethylammonium salt; piretanide cetyltrimethylammonium salt; piretanide N,N-dimethylglycolamide ester; piretanide pivaxetil ester; and piretanide propaxetil ester. 
     
     
         13 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound of formula IV 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer or hydrate thereof, wherein 
         R 3  is selected from the group consisting of: aryl, halo, hydroxy, alkoxy, and aryloxy, unsubstituted or substituted; 
         R 4  and R 5  are each independently selected from the group consisting of: hydrogen, alkylaminodialkyl, alkylhydroxyaminodiakyl, unsubstituted or substituted; and 
         R 6  is selected from the group consisting of alkyloxycarbonylalkyl, alkylaminocarbonyldialkyl, alkylaminodialkyl, alkylhydroxy; a biocompatible polymer, methyloxyalkyl, methyloxyalkaryl, methylthioalkyl and methylthioalkaryl, unsubstituted or substituted. 
       
     
     
         14 . The method of  claim 13 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: tetrazolyl-substituted azosemide; azosemide benzyltrimethylammonium salt; and azosemide cetyltrimethylammonium salt. 
     
     
         15 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist is a compound of formula V 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, tautomer, zwitterion or hydrate thereof, wherein 
         R 7  is selected from the group consisting of: alkyloxycarbonylalkyl, alkylaminocarbonyldialkyl, alkylaminodialkyl, alkylhydroxy, a biocompatible polymer, methyloxyalkyl, methyloxyalkaryl, methylthioalkyl and methylthioalkaryl, unsubstituted or substituted; and 
         X −  is bromide, chloride, fluoride, iodide, mesylate, tosylate; or alternatively, X −  is not present. 
       
     
     
         16 . The method of  claim 15 , wherein the Na + K + 2Cl co-transporter antagonist is a pyridine-substituted torsemide quaternary ammonium salt. 
     
     
         17 . The method of  claim 6 , wherein the Na + K + 2Cl co-transporter antagonist is selected from the group consisting of: bendroflumethiazide; benzthiazide; chlorothiazide; hydrochlorothiazide; hydro-flumethiazide; methylclothiazide; polythiazide; trichloromethiazide; chlorthalidone; indapamide; metolazone; quinethazone; and functional analogs and derivatives thereof. 
     
     
         18 . The method of  claim 1 , wherein the Na + K + 2Cl co-transporter antagonist modulates extracellular ion composition and chloride gradients in nervous system tissue. 
     
     
         19 . The method of  claim 1 , wherein the composition is delivered orally, sublingually, nasally, transdermally, intravenously, intrathecally, or by inhalation. 
     
     
         20 . The method of  claim 1 , wherein the neuropsychiatric disorder is selected from the group consisting of: bipolar disorders; anxiety disorders; depression; and schizophrenia. 
     
     
         21 . The method of  claim 20 , wherein the disorder is an anxiety disorder selected from the group consisting of: panic disorder; social anxiety disorder; obsessive compulsive disorder; posttraumatic stress disorder; generalized anxiety disorder; and specific phobia.