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Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/Oxo‐M ratio as an index of efficacy at cortical muscarinic receptors
Author(s) -
Freedman S.B.,
Harley E.A.,
Iversen L.L.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11451.x
Subject(s) - oxotremorine , chemistry , muscarinic acetylcholine receptor , agonist , carbachol , partial agonist , radioligand , pharmacology , antagonist , pilocarpine , receptor , muscarine , endocrinology , medicine , biochemistry , biology , neuroscience , epilepsy
1 Radioligand binding assays using [ 3 H]‐N‐methylscopolamine (NMS) and [ 3 H]‐oxotremorine M (Oxo‐M) have been devised to predict the efficacy of test compounds at muscarinic receptors in rat cerebral cortex. 2 Muscarinic antagonists, including non‐selective and both M 1 ‐ and M 2 ‐selective compounds, displayed similar affinity for both binding assays. 3 Full agonists such as carbachol and muscarine possessed a ratio of potencies against the antagonist versus the agonist ligand (NMS/Oxo‐M ratio) of > 4000. 4 Compounds which have been shown previously to display partial agonist activity in functional assays e.g. pilocarpine and RS86 had intermediate NMS/Oxo‐M ratios of 100–150. A second group of compounds which included oxotremorine had somewhat higher ratios (500–1400). 5 The ratio of affinity constants for the two assays predicted the ability of agonists to stimulate cortical phosphatidyl‐inositol turnover. 6 These results suggest that the NMS/Oxo‐M ratio may be a useful prediction of efficacy for novel compounds acting at cortical muscarinic receptors.