Theoretical conformational studies of some dopamine antagonistic benzamide drugs: 3-pyrrolidyl- and 4-piperidyl derivatives

Abstract

Model derivatives of 3-pyrrolidyl- and 4-piperidyl-o-methoxybenzamides, as representatives of neuroleptic substituted benzamide drugs, have been investigated by theoretical conformational analysis. Folded conformers of 2-methoxy-N-(1-methyl-3-pyrrolidyl)benzamide have the lowest energy, but extended conformers are only a few kilocalories per mole less stable. As regards to piperidyl derivative, it has been found that folded conformers are of much higher energy than extended ones. These and previous results are discussed in terms of the pharmacologically active conformers of substituted benzamide drugs and of possible modes of interaction with the dopamine receptor.

Molecular structure of benzamide neuroleptics. III. N-(8-Benzyl-1αH,5αH-nortropan-3α-yl)-2,6-dimethoxybenzamide, C23H28N2O3

“…So, as the title compound retains antidopaminergic activity (Delalande Research Centre, 1984), it seems that the neuroleptic power of such molecules is not directly related to the coplanarity of the benzamide moiety and the formation of the intramolecular H bond. This hypothesis is inconsistent with the structure-activity relationships reported for the benzamide neuroleptics ( Van de Waterbeemd & Testa, 1983). The N-benzyl group is in an axial position contrary to the two other analogues previously reported; however, in solution, the two isomers, axial and equatorial, are in equilibrium as observed by 1H NMR.…”

NMR Conformational Study of Aminoalkylbenzamides, Aminoalkyl‐o‐anisamides, and Metoclopramide, a Dopamine Receptor Antagonist

“…The solvent dependence of the intramolecular methoxy-amide H-bond is particulariy interesting. We have recently postulated [7] that the pseudo-cycle resulting from this H-bond is a key feature for the receptor recognition of neuroleptic benzamides. The present work suggests that while such a H-bond does not occur in an aqueous medium, it must indeed exist in a lipophilic environment which is that of membranes and receptors.…”

“…Applying the above correction factor to neuroleptic benzamides of the 2-pyrrolidyl and 3-pyrrolidyl series [6] [7] indicates that these molecules, when in the protonated state and in aqueous solution, must exist in an extended conformation preferred by a few kcal/mol over the folded forms. Globally, neuroleptic benzamides can thus be classified into two groups according to their conformational behaviour in aqueous solution.…”

“…The results indicate that aminoethyl derivatives such as metoclopramide (2) and tiapride (3) exist, without solvent interactions, in a folded (gauche) conformation 10-1 5 kcal/mol more stable than the extended (trans) conformation [5]. In 2-pyrrolidyl derivatives such as sulpiride (1) and 3-pyrrolidyl derivatives such as YM-09151-1 (4), the energy difference is decreased to 3-4 kcal/mol and 5-6 kcal/mol, respectively [6] [7]. In contrast, 4-piperidyl derivatives such as clebopride (5) display the basic side-chain in an extended conformation, the folded forms (boat conformations) being less stable by ca.…”

“…In contrast, 4-piperidyl derivatives such as clebopride (5) display the basic side-chain in an extended conformation, the folded forms (boat conformations) being less stable by ca. 30 kcal/mol [7].…”