Stereoselective inhibition of muscarinic receptor subtypes by the enantiomers of hexahydro‐difenidol and acetylenic analogues

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Abstract
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 (M1), guinea-pig atria (M2) and guinea-pig ileum (M3) 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 M3 receptors: M3 > M2 ≥ M1. 5 These results do not conform to Pfeiffer's rule that activity differences between enantiomers are greater with more potent compounds.