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.

5‐HT4 Receptor Ligands: Applications and New Prospects

“…In particular, (S)-ML-1035, a sulfoxide derivative was described as equipotent to metoclopramide in the enhancement of guinea-pig ileum contraction and rat gastric emptying. 34,35 But more promising results were obtained with the derivatives of metoclopramide, such as BRL 20627, 36 BRL 24682, 37 renzapride, 22 zacopride 21,38 where the amino flexible chain was introduced into a rigid framework such as the quinolizidine, tropane or quinuclidine moieties. These compounds were potent 5-HT3 receptor antagonists of the 5-HT-evoked Bezold-Jarisch reflex and more potent stimulants of the gastrointestinal motility than metoclopramide.…”

5-HT4Receptor Ligands: Applications and New Prospects

“…In particular, (S)-ML-1035, a sulfoxide derivative, was described as equipotent to metoclopramide in the enhancement of guinea pig ileum contraction and rat gastric emptying. 34,35 But more promising results were obtained with the derivatives of metoclopramide, such as BRL 20627, 36 BRL 24682, 37 renzapride, 22 and zacopride, 21,38 where the amino flexible chain was introduced into a rigid framework such as the quinolizidine, tropane, and quinuclidine moieties. These compounds were potent 5-HT 3 receptor antagonists of the 5-HT-evoked Bezold-Jarisch reflex and more potent stimulants of the gastrointestinal motility than metoclopramide.…”

“…The structural modifications of the 2-alkoxy chain of metoclopramide were also claimed to give compounds with potent gastrokinetic properties and weak affinity for the D 2 receptors in the guinea pig and rat. In particular, ( S )-ML-1035, a sulfoxide derivative, was described as equipotent to metoclopramide in the enhancement of guinea pig ileum contraction and rat gastric emptying. , …”