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A novel series of non‐quaternary oxadiazoles acting as full agonists at muscarinic receptors
Author(s) -
Freedman S.B.,
Harley E.A.,
Patel S.,
Newberry N.R.,
Gilbert M.J.,
McKnight A.T.,
Tang J.K.,
Maguire J.J.,
Mudunkotuwa N.T.,
Baker R.,
Street L.J.,
MacLeod A.M.,
Saunders J.,
Iversen L.L.
Publication year - 1990
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.1476-5381.1990.tb14123.x
Subject(s) - muscarinic acetylcholine receptor , oxotremorine , carbachol , chemistry , agonist , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m3 , muscarinic agonist , muscarinic acetylcholine receptor m1 , partial agonist , muscarinic acetylcholine receptor m4 , muscarinic acetylcholine receptor m5 , pharmacology , endocrinology , receptor , biology , biochemistry
1 A novel series of non‐quaternary oxadiazole‐based muscarinic agonists demonstrated high affinity for muscarinic receptors. 2 These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations. 3 Two amino oxadiazoles, one from a quinuclidine series (L‐660,863) and one from a 1‐azanorbornane series (L‐670,207) possessed a high ratio of potency for displacing the binding of [ 3 H]‐N‐methylscopolamine ([ 3 H]‐NMS) to potency for displacing the agonist [ 3 H]‐oxotremorine‐M ([ 3 H]‐oxo‐M) (NMS/oxo‐M ratio) predictive of high efficacy in the cortex. 4 The two azanorbornane derivatives L‐670,548 and L‐670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED 50 0.26 and 0.18 μ m respectively). 5 The maximum response obtained with L‐670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine. 6 These oxadiazole muscarinic agonists are among the most potent and efficacious non‐quaternary muscarinic agonists ever described.