The resolution, isolation, and pharmacological characterization of the enantiomers of a benzamide containing a chiral sulfoxide.
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.
Butler
B T
BT
Department of Pharmacology, Marion Merrell Dow Research Institute-Kansas City Center, Missouri 64137.
Silvey
G
G
Houston
D M
DM
Borcherding
D R
DR
Vaughn
V L
VL
McPhail
A T
AT
Radzik
D M
DM
Wynberg
H
H
ten Hoeve
W
W
van Echten
E
E
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
D001549:Benzamides; D011985:Receptors, Serotonin; C071737:ML 1035; D008787:Metoclopramide