Compositions that preferentially potentiate subtypes of gabaa receptors and methods of use thereof

Abstract

The invention provides compositions containing isomerically pure forms of neurosteroids that permit preferential modulation of different subtypes of GABAA receptors, such as preferential modulation of α4β3δ GABAA receptors over α1β2γ2 GABAA receptors. The invention also provides methods of treating GABAA disorders using such compositions.

What is claimed is: 
     
         1 . A method for treating a GABA A  disorder, the method comprising providing to a subject having a GABA A  disorder a pharmaceutical composition comprising an isomerically pure form of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein the compound of Formula (I) is present in a therapeutically effective amount to preferentially potentiate an α4β3δ GABA A  receptor as compared to an α1β2γ2 GABA A  receptor. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of Formula (I) preferentially positively modulates an α4β3δ GABA A  receptor as compared to an α1β2γ2 GABA A  receptor. 
     
     
         3 . The method of  claim 2 , wherein an EC 50  of the compound of Formula (I) for an α4β3δ GABA A  receptor is less than 50% of an EC 50  of the compound of Formula (I) for an α1β2γ2 GABA A  receptor. 
     
     
         4 . The method of  claim 3 , wherein an EC 50  of the compound of Formula (I) for an α4β3δ GABA A  receptor is less than 20% of an EC 50  of the compound of Formula (I) for an α1β2γ2 GABA A  receptor. 
     
     
         5 . The method of  claim 1 , wherein an EC 50  of the compound of Formula (I) for an α4β3δ GABA A  receptor is less than 500 nM. 
     
     
         6 . The method of  claim 1 , wherein the GABA A  disorder is selected from the group consisting of acute pain, an addictive disorder, Alzheimer's disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington's disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson's disease, a personality disorder, posttraumatic stress disorder (PTSD), psychosis, Rett syndrome, a schizoaffective disorder, schizophrenia, a schizophrenia spectrum disorder, a seizure disorder, a sleep disorder, social anxiety disorder, status epilepticus, stress, stroke, tinnitus, traumatic brain injury (TBI), vascular disease, vascular malformation, vascular type dementia movement disorder, Wilson's disease, and withdrawal syndrome. 
     
     
         7 . The method of  claim 6 , wherein the GABA A  disorder is an epileptic disorder, epileptogenesis, or a seizure disorder. 
     
     
         8 . The method of  claim 1 , wherein the composition is provided orally. 
     
     
         9 . The method of  claim 1 , wherein the composition is provided in a single dose per day. 
     
     
         10 . The method of  claim 1 , wherein the composition is provided in multiple doses per day.