SOLID-STATE CONFORMATIONS AND ANTIDOPAMINERGIC EFFECTS OF REMOXIPRIDE HYDROCHLORIDE AND A CLOSELY RELATED SALICYLAMIDE, FLA 797, IN RELATION TO DOPAMINE RECEPTOR MODELS

Abstract

The X-ray structure of two new 2,6-disubstituted benzamides, i.e., remoxipride hydrochloride monohydrate ((-)-(S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide hydrochloride monohydrate) and FLA 797 ((-)-(S)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamide), have been determined as well as the distribution coefficients. The difference in dopamine receptor blocking activity is discussed in terms of lipophilicity and solid state conformations of the two benzamides. The major difference between the solid state conformations lies in the orientation of carboxamide moiety. In remoxipride the carbonyl group is oriented almost perpendicularly to the benzene ring, thus preventing the formation of a hydrogen-bonded pseudo-ring between the amide hydrogen and the methoxy group found in other types of o-methoxybenzamides. In FLA 797, however, this pseudo-ring is present in the planar conformation of the salicylamide moiety. This conformation is further stabilized by a hydrogen bond between the phenol group and the carbonyl oxygen. The side chain in remoxipride adopts an extended conformation in contrast to FLA 797, where the side chain has a folded conformation. The crystal structures are related to current topographic dopamine receptor models developed from more rigid antidopaminergic compounds. Based on these comparisons. It is suggested that benzamides having an N-ethyl-2-pyrrolidinylmethyl side chain interact with the receptor in the folded conformation. The binding affinity is thought to be further increased by the planar conformation of the salicylamide moiety present in FLA 797, which permits an efficient .pi.-.pi. stacking interaction.