Method of identifying partial agonists of the A2A receptor

Abstract

The present invention provides a method for identifying and using partial adenosine A 2A receptor agonists that are useful as adjuncts in myocardiological perfusion imaging.

We claim:  
     
         1 . A method for identifying compounds that are selective partial A 2A  adenosine receptor agonists with a short duration of action, comprising: 
 a. measuring the intrinsic efficacy of a test compound in a cell line that express adenosine A 2A  receptors.    b. measuring the intrinsic efficacy of a full agonist in said cell line; and    c. selecting those compounds that have a lower intrinsic efficacy than said full agonist;    
     
     
         2 . The method of  claim 1 , comprising the additional steps of measuring the binding affinity (K i ) of the selected compounds; and selecting a compound with a K i 1 μM.  
     
     
         3 . The method of  claim 1 , wherein said test compound is a selective A 2A  adenosine receptor agonist.  
     
     
         4 . The method of  claim 1 , wherein said cell line is rat pheochromocytoma PC12 cells, HEK-293 cells or porcine striatal cells.  
     
     
         5 . The method of  claim 4 , wherein said cell line is rat pheochromocytoma PC 12 cells.  
     
     
         6 . The method of  claim 1 , wherein said full agonist is CGS21680 or WRC 0470.  
     
     
         7 . The method of  claim 6 , wherein said full agonist is CGS21680.  
     
     
         8 . The method of  claim 7 , wherein the intrinsic efficacy of the compound is 10%-95% of the intrinsic efficacy of CGS21680.  
     
     
         9 . The method of  claim 7 , wherein the intrinsic efficacy of the compound is 50%-85% of the intrinsic efficacy of CGS21680.  
     
     
         10 . The method of  claim 1 , wherein said binding affinity of the selected compound is greater than or equal to 1 μM.  
     
     
         11 . A method of myocardial perfusion imaging of a mammal, comprising administering a radionuclide and a compound identified by the method of  claim 1  to a mammal in need thereof, and determining areas of insufficient blood flow.  
     
     
         12 . The method of  claim 11 , wherein the compound is CVT-3033 or CVT-3146.  
     
     
         13 . The method of  claim 12 , wherein the dose of CVT-3033 or CVT-3146 is from 0.20 μg/kg to 9 μg/kg.  
     
     
         14 . The method of  claim 12 , wherein the dose of CVT-3033 or CVT-3146 is 0.25 to 5.0 μg/kg.