A search for selective antagonists at M2 muscarinic receptors

Publisher Website
Google Scholar
Abstract
Isolated preparations of guinea-pig ileum and atria were used to estimate the dose-ratios produced by antagonists at muscarinic receptors. Experiments with 4-diphenyl-acetoxy-N-methylpiperidine (4DAMP) metho-salts and with its isomer, 3DAMPmethiodide, indicated that these were only slightly affected by the choice of physiological salt solution, the choice of agonist and the presence or absence of hexamethonium. Methyl or chloro groups in the p-position of the 2 benzene rings in 4DAMP metho-salts markedly reduce affinity and selectivity. When the 2 benzene rings were linked together, as in the fluorene-9-carboxylic ester, the affinity for the receptors in the atria was comparable with that of 4DAMP methobromide but that for the ileum was about half, so the selectivity is reduced. When the rings were linked as in the xanthene-9-carboxylic ester, the affinity for receptors in both tissues is greater than that of 4DAMP methobromide but there was less selectivity. When 2 molecules of 4DAMP were linked together by a polymethylene chain of from 4-12 C atoms the effects on affinity for muscarinic receptors in the guinea-pig ileum are different from those on affinity for muscarinic receptors in guinea-pig atria. The pentamethylene compound was the most selective: compared with 4DAMP methobromide it had slightly less affinity for receptors in the ileum but much less affinity for receptors in the atria. The effects of the compounds in antagonizing the actions of carbachol on atrial rate were not markedly different from their effects in antagonizing its actions on the force of the atrial contractions.