Conformational analysis of dopamine D-2 receptor antagonists of the benzamide series in relation to a recently proposed D-2 receptor-interaction model.

Conformational analysis using molecular mechanics calculations (MM2(87)) has been performed for four different types of benzamides which display high affinity for the dopamine D-2 receptor. In order to elucidate the conformation of the receptor-bound molecules, a previously described dopamine D-2 receptor-interaction model has been employed. We conclude that all four types of benzamides accommodated in the proposed receptor-interaction model are in low-energy conformations. An acyclic amide side chain is concluded to adopt an extended conformation in the receptor-bound benzamide. A phenylpyrrole analogue of the benzamides could similarly be fitted to the model. Using the receptor-interaction model, the enantioselectivity of benzamides with an N-ethyl-2-pyrrolidinylmethyl side chain could be rationalized in terms of different conformational energies of the receptor-bound enantiomers. Two different receptor sites for N-alkyl substituents are suggested.