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.
Pettersson
I
I
Chemical Center, University of Lund, Sweden.
Liljefors
T
T
D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2