Determination of dissociation constants and relative efficacies of some potent muscarinic agonists at postjunctional muscarinic receptors

Abstract

Summary This study was undertaken to determine dissociation constants (K _A) and relative efficacies (e _r) of seven muscarinic agonists (methylfurtrethonium; dioxolane, oxathiolane, carbachol, muscarine, muscarone and oxotremorine) in three isolated tissues (guinea-pig ileum and atria and rat urinary bladder). The rank order of affinities (-log K _A) of the various compounds varied depending on the tissue used. e _r values for the different agonists did not differ significantly from each other in any of the three tissues, except that the e _r of muscarine in the guinea-pig ileum was higher than those of the other compounds and that of oxotremorine in the rat urinary bladder was lower than those of the other agonists. Comparisons among tissues show that K _A and e _r values were the same in different tissues for some compounds (muscarone, muscarine and methylfurtrethonium), while significant differences were found for the other compounds. This suggests the existence of a discrete receptor population recognized by some but not all agonists. For oxotremorine er as well as -log K _A, is greater in atria than in smooth muscle: these factors combine to determine the cardioselectivity of this compound which can now ascribed to receptor selectivity.