A model for the antagonist binding site on the adenosine A1 receptor, based on steric, electrostatic, and hydrophobic...

With the aid of molecular modeling, both adenosine and adenosine A1 receptor antagonists belonging to various chemical classes were compared with respect to their minimum-energy conformations and molecular electrostatic potentials, as computed by the semiempirical molecular orbital program MOPAC. Distinct steric and electrostatic similarities between adenosine and the prototypic adenosine antagonist theophylline are evident when both compounds are superimposed, with theophylline in a so-called flipped orientation. Similar patterns were found for all other A1 antagonists investigated in this study. A model for the antagonist binding site on the adenosine A1 receptor, based on steric, electrostatic, and hydrophobic properties contributing to potency, is proposed.