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

Abstract

1 Radioligand binding assays using [³H]-N-methylscopolamine (NMS) and [³H]-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 M₁- and M₂-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.