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Stereoselective inhibition of muscarinic receptor subtypes by the enantiomers of hexahydro‐difenidol and acetylenic analogues
Author(s) -
Feifel R.,
WagnerRöder M.,
Strohmann C.,
Tacke R.,
Waelbroeck M.,
Christophe J.,
Mutschler E.,
Lambrecht G.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb12949.x
Subject(s) - vas deferens , enantiomer , muscarinic acetylcholine receptor , chemistry , ileum , methiodide , guinea pig , receptor , stereochemistry , stereoselectivity , muscarinic acetylcholine receptor m2 , stereoisomerism , endocrinology , medicine , pharmacology , biology , biochemistry , catalysis
1 The affinities of the ( R )‐ and ( S )‐enantiomers of hexahydro‐difenidol ( 1 ) and its acetylenic analogues hexbutinol ( 2 ), hexbutinol methiodide ( 3 ) and p‐fluoro‐hexbutinol ( 4 ) (stereochemical purity > 99.8%) for muscarinic receptors in rabbit vas deferens (M 1 ), guinea‐pig atria (M 2 ) and guinea‐pig ileum (M 3 ) were measured by dose‐ratio experiments. 2 The ( R )‐enantiomers consistently showed higher affinities than the ( S )‐isomers. The stereoselectivity ratios [( R )/( S )] were greatest with the enantiomers of 1 (vas deferens: 550; ileum: 191; atria: 17) and least with those of the p ‐Fluoro‐analogue 4 (vas deferens: 34; ileum: 8.5; atria: 1.7). 3 The enantiomeric potency ratios for compounds 1–4 were highest in rabbit vas deferens, intermediate in guinea‐pig ileum and much less in guinea‐pig atria. Thus, these ratios may serve as a predictor of muscarinic receptor subtype identity. 4 ( S )‐ p ‐Fluoro‐hexbutinol [( S ) ‐4 ] showed a novel receptor selectivity profile with preference for M 3 receptors: M 3 > M 2 ≥ M 1 . 5 These results do not conform to Pfeiffer's rule that activity differences between enantiomers are greater with more potent compounds.