THE DESIGN AND PHARMACOLOGY OF NOVEL SELECTIVE MUSCARINIC AGONISTS AND ANTAGONISTS

The muscarinic pharmacology of Cl-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 a nd had higher affinity than the (R)-isomers. The quaternary compound ( S)-BN 228 was found to be the most potent M(1)-selective agonist known today (pEC(50): M(I)/rabbit vas deferens = 7.83; M(2)/guinea-pig atri a = 6.35; M(3)/guinea-pig ileum = 6.29). In both the atria and ileum t he tertiary carbamate, (S)-4-F-MePyMcN, was a competitive antagonist ( pA(2) value = 7.39 and 6.82, respectively). In contrast, in rabbit vas deferens (S)-4-F-MePyMcN was a potent partial agonist (pEC(50) = 7.22 ; apparent efficacy = 0.83). These results indicate that (S)-4-F-MePyM cN might be a useful tool to study M(1) receptor-mediated effects invo lved in central cholinergic function. (S)-Dimethindene was a potent M( 2)-selective antagonist (pA(2) = 7.86/atria; pK(i) = 7.8/rat heart) wi th lower affinities for the M(1) (pA(2) = 6.36/rat duodenum; pK(i) = 7 .1/NB-OK 1 cells), M(3) (pA(2) = 6.92/guinea-pig ileum; pK(i) = 6.7/ra t pancreas) and Mg receptors (pK(i) = 7.0/rat striatum). It was more p otent (up to 41-fold) than the (R)-isomer. In contrast, the stereosele ctivity was inverse at ileal H-1 receptors (pA(2): (R)-isomer = 9.42; (S)-isomer = 7.48). Thus, (S)-dimethindene could be a valuable agent t o test the hypothesis that M(2) antagonists show beneficial effects in the treatment of cognitive disorders. It might also become the starti ng point for the development of diagnostic tools for quantifying M(2) receptors in the CNS with PET imaging.