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. 1990 Nov;101(3):575–580. doi: 10.1111/j.1476-5381.1990.tb14123.x

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

SB Freedman, EA Harley, S Patel, NR Newberry, MJ Gilbert, AT McKnight, JK Tang, JJ Maguire, NT Mudunkotuwa, R Baker, LJ Street, AM MacLeod, J Saunders, LL Iversen
PMCID: PMC1917727  PMID: 2076477

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-methyl-scopolamine ([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.

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Selected References

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