Design, synthesis, and pharmacological properties of new heteroarylpyridine/heteroarylpyrimidine derivatives as CB_2 cannabinoid receptor partial agonists

摘要

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.