title: 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.
authors.affiliation: Department of Pharmacology, Marion Merrell Dow Research Institute-Kansas City Center, Missouri 64137.
authors.forename: B T
authors.initials: BT
authors.lastname: Butler
authors.forename: G
authors.initials: G
authors.lastname: Silvey
authors.forename: D M
authors.initials: DM
authors.lastname: Houston
authors.forename: D R
authors.initials: DR
authors.lastname: Borcherding
authors.forename: V L
authors.initials: VL
authors.lastname: Vaughn
authors.forename: A T
authors.initials: AT
authors.lastname: McPhail
authors.forename: D M
authors.initials: DM
authors.lastname: Radzik
authors.forename: H
authors.initials: H
authors.lastname: Wynberg
authors.forename: W
authors.initials: W
authors.lastname: ten Hoeve
authors.forename: E
authors.initials: E
authors.lastname: van Echten
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008787:Metoclopramide / Q000031:analogs & derivatives*; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D014961:X-Ray Diffraction
chemical_list: D001549:Benzamides; D011985:Receptors, Serotonin; C071737:ML 1035; D008787:Metoclopramide