The design and pharmacology of novel selective muscarinic agonists and antagonists

  • Lambrecht G
  • Gross J
  • Hacksell U
 et al. 
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The muscarinic pharmacology of C1-methyl-substituted chiral compounds related to McN-A-343 and of (R)- and (S)-dimethindene has been studied. Among the McN-A-343 analogues, the (S)-enantiomers were more potent and had higher affinity than the (R)-isomers. The quaternary compound (S)-BN 228 was found to be the most potent M1-selective agonist known today (pEC50: M1/rabbit vas deferens = 7.83; M2/guinea-pig atria = 6.35; M3/guinea-pig ileum = 6.29). In both the atria and ileum the tertiary carbamate, (S)-4-F-MePyMcN, was a competitive antagonist (pA2value = 7.39 and 6.82, respectively). In contrast, in rabbit vas deferens (S)-4-F-MePyMcN was a potent partial agonist (pEC50= 7.22; apparent efficacy = 0.83). These results indicate that (S)-4-F-MePyMcN might be a useful tool to study M1receptor-mediated effects involved in central cholinergic function. (S)-Dimethindene was a potent M2-selective antagonist (pA2= 7.86/atria; pKi= 7.8/rat heart) with lower affinities for the M1(pA2= 6.36/rat duodenum; pKi= 7.1/NB-OK 1 cells), M3(pA2= 6.92/guinea-pig ileum; pKi= 6.7/rat pancreas) and M4receptors (pKi= 7.0/rat striatum). It was more potent (up to 41-fold) than the (R)-isomer. In contrast, the stereoselectivity was inverse at ileal H1receptors (pA2: (R)-isomer = 9.42; (S)-isomer = 7.48). Thus, (S)-dimethindene could be a valuable agent to test the hypothesis that M2antagonists show beneficial effects in the treatment of cognitive disorders. It might also become the starting point for the development of diagnostic tools for quantifying M2receptors in the CNS with PET imaging. © 1995.

Author-supplied keywords

  • (S)-dimethindene
  • McN-A-343 analogues
  • anococcygeus muscle
  • tripitramine

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  • G. Lambrecht

  • J. Gross

  • U. Hacksell

  • U. Hermanni

  • C. Hildebrandt

  • X. Hou

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