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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Butler, BT; Silvey, G; Houston, DM; Borcherding, DR; Vaughn, VL; McPhail, AT; Radzik, DM; Wynberg, H; ten Hoeve, W; van Echten, E

Published Date

  • January 1, 1992

Published In

Volume / Issue

  • 4 / 3

Start / End Page

  • 155 - 162

PubMed ID

  • 1586586

Pubmed Central ID

  • 1586586

Electronic International Standard Serial Number (EISSN)

  • 1520-636X

International Standard Serial Number (ISSN)

  • 0899-0042

Digital Object Identifier (DOI)

  • 10.1002/chir.530040305

Language

  • eng