2-alkynyl-8-aryladenines possessing an amide moiety: Their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A(2B) adenosine receptor

A series of 2-alkynyl-8-aryladenine derivatives bearing an amide moiety at the 9-position of adenine was synthesized. These analogues were evaluated f or inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucos e production in primary cultured rat hepatocytes. The in-primary benzamide derivative 15f was the most potent compound (IC50 = 0.017 PM), being 15-fol d more active than the corresponding 9-methyl derivative (1). Compound 15f showed 72- and 5.2-fold selectivity for human A(2B) receptor versus human A (1) and A(2A) receptors, respectively. Structure-activity relationship (SAR ) studies of the synthesized compounds indicated that a three-carbon linker , fixed in the form of a benzene ring, between the adenine core and the ami de moiety is important for both A(2B) antagonistic activity and selectivity , The IC50 values in rat hepatocyte glucose assay correlated well with the IC50 values in cAMP assay using Chinese hamster ovary cells stably transfec ted with human A(2B) receptors (r(2) = 0.94). The A(1) and A(2A) affinities showed no correlation with the potency to inhibit NECA-induced glucose pro duction. These results strongly support our previous conclusion that adenos ine agonist-induced hepatic glucose production in rat hepatocytes is mediat ed through the A(2B) receptor. (C) 2001 Elsevier Science Ltd. All rights re served.