A DE-NOVO DESIGN PROBE OF A DOPAMINE-RECEPTOR LIGAND BASED ON A THEORETICAL APPROACH

A trial to design de novo a dopamine (DA) receptor ligand was made, ta king as the base four structural and electrostatic requirements: (1) a group simulating the interaction of the DA amino group with the TM3 a spartic acid of the receptor, (2) a group that can simulate the intera ction of the DA m-hydroxyl group with the TM5 serine of the receptor, (3) a distance between these groups similar to that of the DA anti-cop lanar conformer, and (4) a rigid structure keeping the distance betwee n the groups right. After the design ''on paper'' of the models of fou r structures, quantum chemistry calculations were performed to check t he properties of the molecules, and then the most encouraging ones wer e synthesized. None of the compounds synthesized was able to bind D-1- and D-2-dopamine receptor subtypes; this shows that the structural an d electrostatic requirements considered in this work are insufficient. In particular, the presence of an arylethylamine moiety seems to be e ssential for the interaction of a ligand with the DA receptor. (C) 199 6 Academic Press, Inc.