A pharmacophore model for dopamine D4 receptor antagonists

A pharmacophore model for dopamine D-4 antagonists has been developed on the basis of a previously reported dopamine D-2 model. By using exhaustive conformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structurally diverse high affinity D-4 antagonists have successfully been accommodated in the D-4 pharmacophore model. Enantioselectivities may be rationalized by conformational energies required for the enantiomers to adopt their proposed bioactive conformations. The pharmacophore models for antagonists at the D-4 and D-2 receptor subtypes have been compared in order to get insight into molecular properties of importance for D-2/D-4 receptor selectivity. It is concluded that the bioactive conformations of antagonists at the two receptor subtypes are essentially identical. Receptor essential volumes previously identified for the D-2 receptor are shown to be present also in the 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 feature 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 nature of the interactions between the receptor and aromatic ring systems. The effects of the electronic properties of these ring systems on the affinities for the two receptor subtypes differ substantially.