Theoretical structure-activity studies of adenosine A(1) ligands: Requirements for receptor affinity

The three-dimensional (3-D) requirements for A(1) adenosine receptor affinity have been studied based on hydrogen-bonding functionality correlation between a group of twelve A(1) adenosine receptor ligands representing ten structurally different classes of compounds. Electrostatic potential similarity indices and shape similarity indices strongly support the proposed receptor-bound orientations of the ligands. We conclude, in areas common to both agonist and antagonist binding at the A(1) receptor, that the ligands are recognized by a similar physicochemical 3-D environment. The finding of similar 3-D requirements for agonists and antagonists suggests a fairly static receptor structure in the region common to agonist and antagonist binding. The ribose moiety is remote from antagonist binding site. Such a 3-D environment rationalizes the binding of a number of potent novel antagonists including KW-3902, not previously reported in modeling studies. Copyright (C) 1996 Elsevier Science Ltd