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. 1986 Sep;89(1):83–90. doi: 10.1111/j.1476-5381.1986.tb11123.x

Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine.

A Giachetti, E Giraldo, H Ladinsky, E Montagna
PMCID: PMC1917044  PMID: 2432979

Abstract

The selectivity profiles of the muscarinic receptor antagonists dicyclomine and trihexyphenidyl have been examined in binding and functional studies and compared with those of pirenzepine and atropine. Dicyclomine, trihexyphenidyl and pirenzepine demonstrated the highest affinity for the M1 muscarinic receptor subtype as revealed in competition experiments against [3H]-pirenzepine labelling of cortical membranes. Their affinity values lay in a narrow range (3.7-14 nM) approaching that of atropine (1.6 nM). Competition experiments against [3H]-N-methylscopolamine in cardiac and glandular (salivary) membranes revealed differences between the drugs examined. Dicyclomine, trihexyphenidyl and pirenzepine displayed low affinity for the cardiac and intermediate affinity for the glandular receptors. Thus, the drugs appeared to discriminate between the M1 (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC50s varying only slightly (1.6-4.6 nM). The rank order of selectivity was: pirenzepine greater than dicyclomine greater than trihexyphenidyl greater than atropine. Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M1-receptor mediated ganglionic responses (McN A-343 pressor effect in pithed rats and nictitating membrane contraction in cats) than at inhibiting peripheral muscarinic responses in the heart and cardiovascular smooth muscle (vagal bradycardia in rats and cats and vagally-induced vasodilatation in cats). The muscarinic antagonists so far examined can be categorized into two groups. Trihexyphenidyl, dicyclomine and pirenzepine, included in one group, are characterized by a higher affinity for the neuronal (M1) muscarinic receptor, hence they antagonize functional responses mediated by the M1 subtype. Atropine, a member of the other group, shows essentially no selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anwar-ul S., Gilani H., Cobbin L. B. The cardio-selectivity of himbacine: a muscarine receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol. 1986 Jan;332(1):16–20. doi: 10.1007/BF00633191. [DOI] [PubMed] [Google Scholar]
  3. Barlow R. B., Berry K. J., Glenton P. A., Nilolaou N. M., Soh K. S. A comparison of affinity constants for muscarine-sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29 degrees C and in ileum at 29 degrees C and 37 degrees C. Br J Pharmacol. 1976 Dec;58(4):613–620. doi: 10.1111/j.1476-5381.1976.tb08631.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Birdsall N. J., Burgen A. S., Hulme E. C. The binding of agonists to brain muscarinic receptors. Mol Pharmacol. 1978 Sep;14(5):723–736. [PubMed] [Google Scholar]
  5. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  6. Eberlein W., Schmidt G., Reuter A., Kutter E. Das Ulkustherapeutikum Pirenzepin (L-S 519)--eine tricyclische Verbindung mit besonderen physikalisch-chemischen Eigenschaften. Arzneimittelforschung. 1977 Feb;27(2):356–359. [PubMed] [Google Scholar]
  7. Giachetti A., Micheletti R., Montagna E. Cardioselective profile of AF-DX 116, a muscarine M2 receptor antagonist. Life Sci. 1986 May 5;38(18):1663–1672. doi: 10.1016/0024-3205(86)90410-8. [DOI] [PubMed] [Google Scholar]
  8. Giraldo E., Monferini E., Hammer R. Selective labelling of M1-receptors in autonomic ganglia with 3H-pirenzepine. Arzneimittelforschung. 1985;35(1A):325–328. [PubMed] [Google Scholar]
  9. Goyal R. K., Rattan S. Neurohumoral, hormonal, and drug receptors for the lower esophageal sphincter. Gastroenterology. 1978 Mar;74(3):598–619. [PubMed] [Google Scholar]
  10. Hammer R., Berrie C. P., Birdsall N. J., Burgen A. S., Hulme E. C. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature. 1980 Jan 3;283(5742):90–92. doi: 10.1038/283090a0. [DOI] [PubMed] [Google Scholar]
  11. Hammer R., Giachetti A. Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization. Life Sci. 1982 Dec 27;31(26):2991–2998. doi: 10.1016/0024-3205(82)90066-2. [DOI] [PubMed] [Google Scholar]
  12. Hammer R., Giraldo E., Schiavi G. B., Monferini E., Ladinsky H. Binding profile of a novel cardioselective muscarine receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat. Life Sci. 1986 May 5;38(18):1653–1662. doi: 10.1016/0024-3205(86)90409-1. [DOI] [PubMed] [Google Scholar]
  13. Marchi M., Raiteri M. Differential antagonism by dicyclomine, pirenzepine and secoverine at muscarinic receptor subtypes in the rat frontal cortex. Eur J Pharmacol. 1985 Jan 2;107(2):287–288. doi: 10.1016/0014-2999(85)90074-3. [DOI] [PubMed] [Google Scholar]
  14. Stockton J. M., Birdsall N. J., Burgen A. S., Hulme E. C. Modification of the binding properties of muscarinic receptors by gallamine. Mol Pharmacol. 1983 May;23(3):551–557. [PubMed] [Google Scholar]
  15. Tien X. Y., Wallace L. J. Trihexyphenidyl--further evidence for muscarinic receptor subclassification. Biochem Pharmacol. 1985 Feb 15;34(4):588–590. doi: 10.1016/0006-2952(85)90196-0. [DOI] [PubMed] [Google Scholar]
  16. Watson M., Roeske W. R., Yamamura H. I. [3h]pirenzepine selectively identifies a high affinity population of muscarinic cholinergic receptors in the rat cerebral cortex. Life Sci. 1982 Nov 1;31(18):2019–2023. doi: 10.1016/0024-3205(82)90041-8. [DOI] [PubMed] [Google Scholar]
  17. Yamamura H. I., Watson M., Wamsley J. K., Johnson P. C., Roeske W. R. Light microscopic autoradiographic localization of [3H]pirenzepine and [3H](-)quinuclidinyl benzilate binding in human stellate ganglia. Life Sci. 1984 Aug 13;35(7):753–757. doi: 10.1016/0024-3205(84)90344-8. [DOI] [PubMed] [Google Scholar]

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