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.
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 greater than 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.
Freedman
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SB
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
Harley
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EA
Iversen
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LL
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D008297:Male; D019832:N-Methylscopolamine; D010095:Oxotremorine / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011950:Receptors, Cholinergic / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012602:Scopolamine Derivatives / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D010743:Phospholipids; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D007294:Inositol; D010095:Oxotremorine; D019832:N-Methylscopolamine