CoMFA-based comparison of two models of binding site on adenosine A1 receptor.

A set of 32 N6-substituted adenosines and 22 8-substituted xanthines with affinity for adenosine A1 receptors was subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis (CoMFA). The aim was to compare two modes of binding to the receptor--'N6-C8' and 'N6-N7'. Good models with high predictive power and stability were obtained. A comparison of these models gives the following results: (a) Inclusion of both steric and electrostatic fields in CoMFA generates better predictive models compared to models based on steric or electrostatic fields alone. (b) The 'N6-N7' CoMFA models are slightly better than the 'N6-C8' ones. (c) Steric restriction exists around the N6-H in the 'N6-N7' steric field map, which is absent in the 'N6-C8' steric field map. This report demonstrates that the 'N6-N7' mode of binding is a further development of the 'N6-C8' model with a slightly better predictive ability and more accurate steric and electrostatic overlaps between agonists and antagonists.