Design, synthesis, and pharmacological properties of new heteroarylpyridine/heteroarylpyrimidine derivatives as CB(2) cannabinoid receptor partial agonists.

Recent developments indicate that CB(2) receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB(2) receptor. Very recently, we have identified the oxazinoquinoline carboxamides as a novel class of CB(2) receptor full agonists. In this paper we describe the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives. Some of the reported compounds showed high affinity and potency at the CB(2) receptor while showing only modest affinity for the centrally expressed CB(1) cannabinoid receptor. Moreover, we found that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series show dose-dependent effects on the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists, and inverse agonists.