A pharmacophore model for dopamine D-4 receptor antagonists

A pharmacophore model for dopamine D-4 antagonists has been developed on th e basis of a previously reported dopamine D-2 model. By using exhaustive co nformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structur ally diverse high affinity D-4 antagonists have successfully been accommoda ted in the D-4 pharmacophore model. Enantioselectivities may be rationalize d by conformational energies required for the enantiomers to adopt their pr oposed bioactive conformations. The pharmacophore models for antagonists at the D-4 and D-2 receptor subtypes have been compared in order to get insig ht into molecular properties of importance for D-2/D-4 receptor selectivity . It is concluded that the bioactive conformations of antagonists at the tw o receptor subtypes are essentially identical. Receptor essential volumes p reviously identified for the D-2 receptor are shown to be present also in t he D-4 receptor. In addition, a novel receptor essential volume in the D-4 receptor, not present in the D-2 receptor, has been identified. This featur e may be exploited for the design of D-4 selective antagonists. However, it is concluded that the major determinant for D-2/D-4 selectivity is the nat ure of the interactions between the receptor and aromatic ring systems. The effects of the electronic properties of these ring systems on the affiniti es for the two receptor subtypes differ substantially.