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

We have built a model of the D-2 dopaminergic receptor protein and have doc ked 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-fluoro propyl)- 2,3-dimethoxybenzamide (ZYY-106), to its putative active site. We have utilized the structures of bacteriorhodopsin and rhodopsin for modelin g the D-2 receptor by homology. Mutation studies and structure-activity stu dies have been used to refine our model further. Docking exercises of the l igands 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 as partate 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 si gnificant interaction of the phenyl ring of fallypride was observed with Ph e121 and Trp155, which was weaker in the case of dopamine. The N-allyl grou p of fallypride is flanked by Phe158 and His162, possibly enhancing - inter action and the fluoropropyl group in fallypride is flanked by helix5: Pro12 4, helix5: phe125 and helix3: Ile75, which seem to form a pocket. These int eractions may account for the higher affinity of fallypride for the D-2 rec eptor compared to dopamine.