Conformational Analysis of Dopamine D-2 Receptor Antagonists of the Benzamide Series in Relation to a Recently Proposed D-2 Receptor-Interaction Model

J Med Chem. 1992 Jun 26;35(13):2355-63. doi: 10.1021/jm00091a002.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Receptors, Dopamine / drug effects*
  • Receptors, Dopamine D2
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Receptors, Dopamine
  • Receptors, Dopamine D2