Stereoselective inhibition of muscarinic receptor subtypes by the enantiomers of hexahydro-difenidol and acetylenic analogues.
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 greater than 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 greater than M2 greater than or equal to M1. 5. These results do not conform to Pfeiffer's rule that activity differences between enantiomers are greater with more potent compounds.
Feifel
R
R
Department of Pharmacology, University of Frankfurt, Federal Republic of Germany.
Wagner-Röder
M
M
Strohmann
C
C
Tacke
R
R
Waelbroeck
M
M
Christophe
J
J
Mutschler
E
E
Lambrecht
G
G
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects
D000480:Alkynes; D010880:Piperidines; D011976:Receptors, Muscarinic; C060685:hexahydrodifenidol; C063963:hexbutinol; C063965:hexbutinol methiodide; C063966:4-fluorohexbutinol