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The action of (±)L-660,863 [(±)3-(3-amino-1,2,4-oxadiazole-5-yl)-quinuclidine] at muscarinic receptor subtypes in vitro

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Summary

  1. 1.

    The muscarinic pharmacology of a novel oxadiazole muscarinic agonist, (±) L-660,863, [±3-(3-amino- 1,2,4-oxadiazole-5-yl)-quinuclidine] has been studied using pharmacological, radioligand binding and biochemical techniques, in vitro.

  2. 2.

    In isolated tissue experiments, (±)L-660,863 was a more potent agonist than carbachol in all preparations studied, being most potent at muscarinic receptors mediating negative chronotropy in guinea-pig right, spontaneously beating atria and least potent at receptors mediating contractions in canine saphenous vein and endothelial denuded rabbit aorta (-log EC50) values were 8.8, 6.6 and 6.3, respectively. The apparent affinities (-log KA) of (±)L-660,863, estimated by receptor inactivation, showed some selectivity toward the atrial M2 muscarinic receptor (-log KA = 7.6) in comparison to the M1 or M3 muscarinic receptors (-log KA = 5.4 and 6.2), respectively. This degree of selectivity was also observed in competition radioligand binding studies.

  3. 3.

    At M3 muscarinic receptors mediating inositol phosphates (IPs) accumulation in longitudinal muscle of guinea-pig ileum, the potency of (00B1;)L-660,863 (-log EC50 value = 6.2) was similar to the apparent affinity calculated at M3 muscarinic receptors in the functional studies (see above). In contrast, at muscarinic receptors mediating IPs accumulation in guinea-pig atria and ventricles, the potency for (±)L-660,863 (-log EC50 = 6.2 and 6.4, respectively) was lower than the apparent affinity calculated at M2 muscarinic receptors from inotropic and binding studies in cardiac tissue (see above). These data suggest that the concentration-occupancy curve for (±)L-660,863 at cardiac muscarinic receptors mediating IPs accumulation lies to the right of the concentration-response curve. Similar conclusions may be made with regard to contraction by (±)L-660,863 of endothelial denuded rabbit aorta mediated by M2 receptors (Jaiswal et al. 1991). These findings may imply differences between muscarinic receptors mediating negative inotropy and IPs accumulation in guinea-pig myocardium or contraction of endothelial denuded rabbit aorta.

  4. 4.

    (±)L-660,863, in conclusion, acted as a potent muscarinic agonist, with some degree of M2 muscarinic receptor selectivity M2 VS M1 - 160 fold; M2 vs M3 - 25 fold \3- the first muscarinic agonist with, such a profile of activity. This compound may provide a useful tool with which to characterize muscarinic receptor function, as evidenced by the biochemical studies in cardiac tissue.

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Authors and Affiliations

  1. Institute of Pharmacology, 3401 Hillview Avenue, 94304, Palo Alto, CA, USA

    R. M. Eglen, G. C. Harris, A. P. D. W. Ford, E. H. F. Wong & R. L. Whiting

  2. Institute of Organic Chemistry, Syntex Research, 3401 Hillview Avenue, 94304, Palo Alto, CA, USA

    J. R. Pfister

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  1. R. M. Eglen
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  2. G. C. Harris
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  3. A. P. D. W. Ford
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  4. E. H. F. Wong
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  5. J. R. Pfister
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  6. R. L. Whiting
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Eglen, R.M., Harris, G.C., Ford, A.P.D.W. et al. The action of (±)L-660,863 [(±)3-(3-amino-1,2,4-oxadiazole-5-yl)-quinuclidine] at muscarinic receptor subtypes in vitro. Naunyn-Schmiedeberg's Arch Pharmacol 345, 375–381 (1992). https://doi.org/10.1007/BF00176613

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  • DOI: https://doi.org/10.1007/BF00176613

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