2-Alkynyl-8-aryl-9-methyladenines as novel adenosine receptor antagonists : Their synthesis and structure-activity relationships toward hepatic glucose production induced via agonism of the A2B receptor

Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives, were synthesized as candidate hypoglycemic agents. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. In general, aromatic moieties at the 8-position and alkynyl groups at the 2-position had significantly increased activity compared to unsubstituted compounds. The preferred substituents at the 8-position of adenine were the 2-furyl and 3-fluorophenyl groups. In modifying the alkynyl side chain, change of the ring size, cleavage of the ring, and removal of the hydroxyl group were well tolerated. The order of the stimulatory effects of adenosine agonists on rat hepatocytes was NECA > CPA > CGS21680, which is consistent with involvement of the A2B receptor. In Chinese hamster ovary cells stably transfected with human A2B receptor cDNA, one of the compounds potent in hepatocytes, 15o (IC50 = 0.42 μM), antagonized NECA-induced stimu...