Stereoselective inhibition of muscarinic receptor subtypes by the eight stereoisomers related to rociverine

Pascaline Barbier, Anna R. Renzetti, Luigi Turbanti, Cristina Di Bugno, Francesco Fornai, Francesca Vaglini, Roberto Maggio, Giovanni U. Corsini

Research output: Contribution to journalArticlepeer-review

Abstract

The chemical structure corresponding to 1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid 2-(diethylamino)-1-methylethyl ester has the classical profile of ester-type antimuscarinic drugs. The presence of three chiral carbons leads to eight stereoisomers and the substitutions on the cyclohexyl ring generate cis-isomers (1, named rociverine and trans-isomers (2). The aim of this study was to determine the binding pattern of the eight stereoisomers and two derived compounds, (1S,2S)-1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid 2-(dimethylamino)-1-ethyl ester (3) and (1S,2S)-1-hydroxy[1,1′-bicyclohexyl]-2-carboxylic acid (S)-2-(diethylamino)-1-methylethyl ester methyl iodide (4), at the five cloned muscarinic receptors stably expressed in chinese hamster ovary cells, in order to define how stereochemical modifications could affect the affinity. Our data showed that cis-stereoisomers exhibited higher variations in affinity than trans-stereoisomers. Among the cis-stereoisomers, those with the (1R,2R) configuration showed considerably higher affinities (up to 240-fold) than those with the (1S,2S) configuration. The (1S,2S) configuration was important for binding selectivity; this was confirmed also by the use of the two additional compounds.

Original languageEnglish
Pages (from-to)125-132
Number of pages8
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Volume290
Issue number2
DOIs
Publication statusPublished - Jul 18 1995

Keywords

  • Binding affinity
  • CHO (Chinese hamster ovary) cells
  • Muscarinic receptors
  • Pirenzepine
  • Stereoselectivity

ASJC Scopus subject areas

  • Pharmacology

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