CB1 Receptor Antagonists and Uses Thereof

Abstract

Neutral antagonists of the CB1 cannabinoid receptor, means for identifying neutral antagonists of the CB1 cannabinoid receptor, and uses thereof. Antagonists of the CB1 cannabinoid receptor can be used to prevent, treat or reduce the severity of various medical conditions and symptoms, including, but not limited to obesity, appetite disorder, another metabolic disorder, drug addiction and/or mental illness. Administering neutral CB1 cannabinoid receptor antagonists in place of or in combination with known CB1 cannabinoid receptor antagonists or inverse CB1 cannabinoid receptor agonists in an individual or animal to treat a medical condition with a reduction of unwanted side effects. A method of detecting a neutral CB1 cannabinoid receptor antagonist, including identifying a candidate compound; subjecting the candidate compound to one or more of a cAMP assay, CB1 competitive binding assay, food intake assay, thermoregulation assay, or emesis assay; and selecting the compound if it exhibits neutral antagonist activity.

What is claimed is: 
     
         1 . (canceled) 
     
     
         2 . A neutral antagonist and physiologically acceptable salts thereof having at least one of the following properties:
 (a) having essentially no effect on intracellular cyclic adenosine monophosphate levels after binding to the CB1 cannabinoid receptors;   (b) having binding selectivity for CB1 cannabinoid receptors over the CB2 cannabinoid receptors within the range of about 10 to about 1000 fold;   (c) reducing food intake or weight gain by about 10 to about 70 percent when administered in a therapeutically effective amount in vivo;   (d) showing essentially no increase in emesis or nausea when administered in a therapeutically effective amount in vivo.   
     
     
         3 . The neutral antagonist of  claim 2  being a congener having about the same molecular weight as Compound 2 or Compound 3: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The neutral antagonist of  claim 2  being a congener having about the same molecular weight as Compound 1: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The neutral antagonist of  claim 2  having essentially no effect on the intrinsic receptor activity. 
     
     
         6 . The neutral antagonist of  claim 2  capable of modulating CB1 receptor binding and activation in an individual or an animal without substantially modulating activity of the receptor. 
     
     
         7 . The neutral antagonist of  claim 2  having the chemical structure of: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is O or CH 2 ; 
 Z is an aromatic heterocyclic ring containing from about 5 to about 7 ring atoms, or a nonaromatic heterocyclic ring containing from about 5 to about 7 ring atoms; or 
 Z is an aromatic heterocyclic ring containing 6 ring atoms and the —C≡CCH 2 CH 2 CN is bonded to the ring in the para position, or 
 Z is a nonaromatic heterocyclic ring containing 6 ring atoms and the —C≡CCH 2 CH 2 CN is bonded to the ring in the para position, and physiologically acceptable salts and derivatives thereof. 
 
     
     
         8 . A method of modulating CB1 receptor binding and activation in an individual or an animal without substantially modulating activity of the receptor, the method comprising administering to the individual or animal a therapeutically effective amount of at least one of the neutral antagonists of  claim 2 . 
     
     
         9 . A method to treat, prevent or reduce a condition chosen from one or more of obesity; appetite disorders; cardiovascular disorders; a metabolic disorder selected from one or more of diabetes, elevated LDL, elevated cholesterol, and low HDL; addiction to drugs of abuse consisting of cannabis, nicotine, cocaine, and/or opiates; loss of cognition and memory; and schizophrenia in an animal or individual having that condition comprising administering to the individual or animal in need of same a therapeutically effective amount of at least one of the neutral antagonists of  claim 2 . 
     
     
         10 . The method of  claim 9 , comprising administering to the individual or animal in need of same a therapeutically effective amount of at least one of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in combination with at least one of the neutral antagonists of  claim 2 . 
     
     
         11 . The method of  claim 9 , comprising the individual adopting a lifestyle choice to lose or maintain weight concurrently with administration of at least one of the neutral antagonists of  claim 2 .