A novel series of non‐quaternary oxadiazoles acting as full agonists at muscarinic receptors

Abstract

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 [³H]-N-methylscopolamine ([³H]-NMS) to potency for displacing the agonist [³H]-oxotremorine-M ([³H]-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 (ED₅₀ 0.26 and 0.18 μm 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.