Gabaergic ligands and their uses

Abstract

Described herein are α3 or α2 or α2/α3 GABAergic receptor subtype selective ligands, pharmaceutical compositions, and methods of use of such ligands and compositions in treatment of anxiety disorders, epilepsy and schizophrenia with reduced sedative and ataxic side effects. In embodiments, such as α3 or α2 or α2/α3 GABAergic receptor subtype selective ligands lack ester linkages and may be thus relatively insensitive to hydrolysis by esterases.

1 - 18 . (canceled) 
     
     
         19 . A method of treating Dravet syndrome in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound is or 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19 , wherein said pharmaceutical composition is administered by enteral or parenteral administration. 
     
     
         21 . The method of  claim 19 , wherein said compound or a pharmaceutically acceptable salt thereof is administered at a dosage level of from 0.01 to 250 mg/kg a day. 
     
     
         22 . The method of  claim 19 , wherein said compound or a pharmaceutically acceptable salt thereof is administered at a dosage level of from 0.01 to 100 mg/kg a day. 
     
     
         23 . The method of  claim 19 , wherein said compound or a pharmaceutically acceptable salt thereof is administered at a dosage level of from 0.01 to 5 mg/kg a day. 
     
     
         24 . The method of  claim 19 , wherein said pharmaceutical composition is administered 1 to 4 times per day. 
     
     
         25 . The method of  claim 19 , wherein said pharmaceutical composition is administered in a unit dosage form. 
     
     
         26 . The method of  claim 19 , wherein said pharmaceutical composition is administered as a tablet, pill, capsule, powder, granule, sterile parenteral solution or suspension, metered aerosol, liquid spray, drop, ampoule, auto-injector formulation, suppository, buccal formulation, or transdermal patch. 
     
     
         27 . The method of  claim 19 , wherein said pharmaceutical composition comprises a crystal of said compound or a salt thereof. 
     
     
         28 . The method of  claim 19 , wherein said compound is 
       
         
           
           
               
               
           
         
       
     
     
         29 . The method of  claim 19 , wherein said compound is 
       
         
           
           
               
               
           
         
       
     
     
         30 . A method of modulating an activity of a GABAA receptor in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound is or 
       
         
           
           
               
               
           
         
       
       and
 wherein said subject has one or more syndromes selected from the group consisting of: Childhood absence epilepsy (CEA), Juvenile absence epilepsy, Juvenile myoclonic epilepsy (JME), West syndrome, Dravet syndrome, and Lennox-Gastaut syndrome (LGS). 
 
     
     
         31 . The method of  claim 30 , wherein said subject has Dravet syndrome. 
     
     
         32 . A pharmaceutical composition comprising:
 (a). a compound or a pharmaceutically acceptable salt thereof, and   (b). a carrier or excipient that comprises a surfactant or an antifoam, wherein said compound is   
       
         
           
           
               
               
           
         
       
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein said carrier or excipient comprises a surfactant. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein said surfactant is Tween 80. 
     
     
         35 . The pharmaceutical composition of  claim 32 , wherein said carrier or excipient comprises an antifoam. 
     
     
         36 . The pharmaceutical composition of  claim 32 , wherein said carrier or excipient comprises cellulose. 
     
     
         37 . The pharmaceutical composition of  claim 32 , wherein said pharmaceutical composition comprises from 1% to 95% of active ingredient. 
     
     
         38 . A method of treating Dravet syndrome in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound is 
       
         
           
           
               
               
           
         
       
       or a deuterium or tritium isotope enriched derivative thereof.