Endogenous, constitutively activated G protein-coupled orphan receptors

Abstract

Disclosed herein are techniques for directly identifying candidate compounds as agonists, partial agonists and/or, most preferably, inverse agonists, to endogenous, constitutively activated orphan G protein-coupled receptors. Such directly identified compounds can be utilized, most preferably, in pharmaceutical compositions.

What is claimed is:  
     
         1 . A method for directly identifying a candidate compound as a compound selected from the group consisting of an inverse agonist, a partial agonist and an agonist, to an endogenous, constitutively active G protein coupled orphan receptor, comprising the steps of: 
 (a) contacting a candidate compound with GPCR Fusion Protein, said GPCR Fusion Protein comprising an endogenous, constitutively active G protein coupled orphan receptor and a G protein; and    (b) determining, by measurement of the compound efficacy at said contacted receptor, whether said compound is an inverse agonist, a partial agonist or an agonist of said receptor.    
     
     
         2 . The method of  claim 1  wherein the compound is directly identified as an inverse agonist to said orphan receptor.  
     
     
         3 . The method of  claim 1  wherein the compound is directly identified as an agonist to said orphan receptor.  
     
     
         4 . The method of  claim 1  wherein the compound is directly identified as partial agonist to said orphan receptor.  
     
     
         5 . A composition comprising a compound identified by the method of  claim 2 .  
     
     
         6 . A composition comprising a compound identified by the method of  claim 3 .  
     
     
         7 . A composition comprising a compound identified by the method of  claim 4 .  
     
     
         8 . The method of  claim 1  wherein said orphan receptor is selected from the group consisting of: GPR3, GPR4, GPR6, GPR12, GPR21, OGR1, GHSR, RE2 and ALO22171.  
     
     
         9 . The method of  claim 1  wherein said orphan receptor is GPR6.  
     
     
         10 . The method of  claim 1  wherein said G protein is selected from the group consisting of: Gs, Gi, Gq and Go.  
     
     
         11 . The method of  claim 1  wherein said G protein is Gsα.  
     
     
         12 . A method for directly identifying a candidate compound as a compound selected from the group consisting of an inverse agonist, a partial agonist and an agonist, to an endogenous, constitutively active G protein coupled orphan receptor, comprising the steps of. 
 (a) contacting a candidate compound with GPCR Fusion Protein, said GPCR Fusion Protein comprising an endogenous, constitutively active G protein coupled orphan receptor and a Gsα protein; and    (b) determining, by measurement of the compound efficacy at said contacted receptor, whether said compound is an inverse agonist, a partial agonist or an agonist of said receptor.    
     
     
         13 . The method of  claim 12  wherein said orphan receptor is selected from the group consisting of: GPR3, GPR4, GPR6, GPR12, GPR21, OGR1, GHSR, RE2 and ALO22171.  
     
     
         14 . The method of  claim 12  wherein said orphan receptor is GPR6.  
     
     
         15 . The method of  claim 14  wherein said compound is directly identified as a compound selected from the group consisting of an inverse agonist and an agonist.  
     
     
         16 . The method of  claim 15  wherein said compound is an inverse agonist.  
     
     
         17 . A composition comprising the compound of  claim 16 .  
     
     
         18 . A method for modulating a G protein coupled oprhan receptor comprising the step of contacting said receptor with a compound identified by the method of  claim 1 .  
     
     
         19 . A method for modulating a G protein coupled oprhan receptor comprising contacting said receptor with a compound identified by the method of  claim 12.