Comparison of the interaction of dopamine and high affinity positron emission tomography radiotracer fallypride with the dopamine D-2 receptor: a molecular modeling study

Abstract

We have built a model of the D-2 dopaminergic receptor protein and have docked the agonist dopamine and two dopamine D-2 receptor antagonists, (S)-N-[(1-allyl-2-pyrrolidinyl)- methyl]-5-(3-fluoropropyl)-2,3-dimethoxybenzamide (fallypride) and (S)-N-[(1-iso-butyl- 2-pyrrolidinyl)methyl]-5-(3-fluoropropyl)-2,3-dimethoxybenzamide (ZYY-106), to its putative active site. We have utilized the structures of bacteriorhodopsin and rhodopsin for modeling the D-2 receptor by homology. Mutation studies and structure-activity studies have been used to refine our model further. Docking exercises of the ligands to the computer-generated D-2 model are used to explain the observed in vitro and in vivo behavior of these compounds. Interactions with the aspartate residue (Asp67) in helix-3 and the serine residues (serine-117 and serine-120) in helix-5 were observed for both dopamine and fallypride. A significant interaction of the phenyl ring of fallypride was observed with Phe121 and Trp155, which was weaker in the case of dopamine. The N-allyl group of fallypride is flanked by Phe158 and His162, possibly enhancing π-π interaction and the fluoropropyl group in fallypride is flanked by helix5:Pro124, helix5:phe125 and helix3:Ile75, which seem to form a pocket. These interactions may account for the higher affinity of fallypride for the D-2 receptor compared to dopamine.