Inhibitors of agonist-specific desensitization

Abstract

The present invention relates to a method of inhibiting desensitization of a cell to the effects of a compound. The method comprises contacting the cell with an agent capable of inhibiting phosphorylation, by a protein kinase, of a receptor for the compound present on the surface of the cell. The present invention also relates to a method of screening a compound for its ability to inhibit desensitization. The method comprises: i) contacting a receptor specific kinase-containing sample with the compound under conditions such that interaction between receptor specific kinase present in the sample and the compound can occur, and ii) determining the ability of the receptor specific kinase to phosphorylate the receptor for which it is specific.

What is claimed is:  
     
         1 . A method of inhibiting desensitization of a cell to the effects of a compound comprising contacting said cell with an agent capable of inhibiting phosphorylation, by a protein kinase, of a receptor for said compound present on the surface of said cell.  
     
     
         2 . The method according to  claim 1  wherein said desensitization is homologous desensitization.  
     
     
         3 . The method according to  claim 1  wherein said compound is an endogenous compound.  
     
     
         4 . The method according to  claim 1  wherein said compound is a drug.  
     
     
         5 . The method according to  claim 1  wherein said receptors are β 2  adrenergic receptors.  
     
     
         6 . The method according to  claim 1  wherein said protein kinase is β adrenergic receptor kinase.  
     
     
         7 . The method according to  claim 1  wherein said cell is a human cell.  
     
     
         8 . A method of screening a compound for its ability to inhibit desensitization comprising: 
 i) contacting a receptor specific kinase-containing sample with said compound under conditions such that interaction between receptor specific kinase present in said sample and said compound can occur, and    ii) determining the ability of said receptor specific kinase to phosphorylate the receptor for which it is specific.    
     
     
         9 . The method according to  claim 8  wherein said receptor specific kinase is β adrenergic receptor kinase.  
     
     
         10 . The method according to  claim 8  wherein said desensitization is homologous desensitization.  
     
     
         11 . The method according to  claim 8  wherein said receptor specific kinase containing sample is derived from a human source.  
     
     
         12 . An inhibitor of β adrenergic receptor kinase consisting essentially of a peptide corresponding to an intracellular domain of the β 2 adrenergic receptor.  
     
     
         13 . The inhibitor according to  claim 12  wherein said peptide is selected from the group consisting residues 56-74, residues 57-71 and residues 219-234.  
     
     
         14 . A pharmaceutical composition comprising as an active ingredient a peptide according to  claim 12  in an amount sufficient to exhibit an inhibitory effect on β adrenergic receptor kinase, together with a pharmaceutically acceptable carrier.