Anilides related to substituted benzamides. Potential antipsychotic activity of N-(4-amino-5-chloro-2-methoxyphenyl)-1-(phenylmethyl)-4-piperidinecarboxamide

Abstract

The substituted benzamides are used clinically both as antipsychotics and as stimulants of gastric motility. The antipsychotic effects are considered to be a consequence of their central dopamine antagonist properties but there is evidence that the gastric stimulatory effects may be mediated by other mechanisms. Clebopride (3) is a substituted benzamide that although marketed for its stimulatory effects on gastric motility, is also a potent central dopamine antagonist. The corresponding anilide, BRL 20596 [N-(4-amino-5-chloro-2-methoxyphenyl)-1-(phenylmethyl)-4-piperidinecarboxamide] (4a), where the amide bond has been reversed, was synthesized and found to lacked stimulatory activity. The potent central dopamine antagonist activity was retained, suggesting that benzamides and anilides have similar affinities for central dopamine receptors; [both 3 and 4a antagonized apomorphine-induced climbing in mice]. The implications of the conformations adopted by benzamides and anilides at such receptors are discussed. There may be a further lipophilic binding site on such receptors for which the N-benzyl group is an optimal fit.