The resolution, isolation, and pharmacological characterization of the enantiomers of a benzamide containing a chiral sulfoxide

Abstract

Rac-ML-1035 (MDL 201,035: 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl] benzamide hydrochloride) is a racemic gastroprokinetic with serotonergic (5-hydroxytryptamine, 5-HT) activity and a novel chiral sulfoxide substituent. Chromatographic and chemical methods have been developed to resolve the enantiomers of rac-ML-1035, and the absolute configuration of the (R)-enantiomer has been determined. We also report pharmacological characterization of rac-ML-1035 and its respective isomers. Radioligand binding to rat cortical membranes revealed that (R)-ML-1035 (MDL 201,226) and (S)-ML-1035 (MDL 201,227) had equivalent activity at the 5-HT3 receptor. However, in isolated tissue studies including field-stimulated guinea pig ileum, field-stimulated rat fundic strip, and nonstimulated guinea pig ileum, (S)-ML-1035 was equally potent yet had greater maximal activity than (R)-ML-1035 in eliciting or facilitating cholinergic contractions. Thus, enantiomers of rac-ML-1035 can be resolved, and the relative configuration of these isomers influences their pharmacological activity.