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, taking as the base four structural and electrostatic requirements: (1) a group simulating the interaction of the DA amino group with the TM3 aspartic acid of the receptor, (2) a group that can simulate the interaction 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-coplanar conformer, and (4) a rigid structure keeping the distance between the groups right. After the design ''on paper'' of the models of four structures, quantum chemistry calculations were performed to check the properties of the molecules, and then the most encouraging ones were synthesized. None of the compounds synthesized was able to bind D-1- and D-2-dopamine receptor subtypes; this shows that the structural and electrostatic requirements considered in this work are insufficient. In particular, the presence of an arylethylamine moiety seems to be essential for the interaction of a ligand with the DA receptor. (C) 1996 Academic Press, Inc.