Probing distal regions of the A2B adenosine receptor by quantitative structure-activity relationship Modeling of known and novel agonists

The binding modes at the A(2B) adenosine receptor (AR) of 72 derivatives of adenosine and its 5'-N-methyluronamide with diverse substitutions at the 2 and N-6 positions were studied using a molecular modeling approach. The compounds in their receptor-docked conformations were used to build CoMFA and CoMSIA quantitative structure-activity relationship models. Various parameters, including different types of atomic charges, were examined. The best statistical parameters were obtained with a joint CoMFA and CoMSIA model: R-2 = 0.960, Q(2) = 0.676, SEE = 0.175, F = 158, and R-test(2) = 0.782 for an independent test set containing 18 compounds. On the basis of the modeling results. four novel adenosine analogues, having elongated or bulky substitutions at N-6 position and/or 2 position, were synthesized and evaluated biologically. All of the proposed compounds were potent, full agonists at the A(2B) AR in adenylate cyclase studies. Thus, in support of the modeling, bulky substitutions at both positions did not prevent A(2B) AR activation, which predicts separate regions for docking of these moieties.