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The resolution, isolation, and pharmacological characterization of the enantiomers of a benzamide containing a chiral sulfoxide
Author(s) -
Butler Brent T.,
Silvey Gary,
Michael Houston D.,
Borcherding David R.,
Vaughn Valerie L.,
McPhail Andrew T.,
Radzik Donna M.,
Wynberg Hans,
Ten Hoeve W.,
Van Echten E.,
Ahmed Nahed K.,
Linnik Matthew D.
Publication year - 1992
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530040305
Subject(s) - chemistry , benzamide , enantiomer , sulfoxide , stereochemistry , hydrochloride , cholinergic , biological activity , substituent , serotonin , serotonergic , guinea pig , receptor , biochemistry , in vitro , organic chemistry , medicine
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‐HT 3 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. © 1992 Wiley‐Liss, Inc.