Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1991 Jun;103(2):1561–1567. doi: 10.1111/j.1476-5381.1991.tb09827.x

Modulation of the structure-binding relationships of antagonists for muscarinic acetylcholine receptor subtypes.

E K Pedder 1, P Eveleigh 1, D Poyner 1, E C Hulme 1, N J Birdsall 1
PMCID: PMC1908365  PMID: 1884110

Abstract

1. Membranes from rat cerebral cortex, myocardium and extraorbital lacrimal gland were used as sources of M1, M2 and M3 muscarinic acetylcholine receptors respectively and the affinities of seven antagonists for the three subtypes were examined under different experimental conditions. 2. The affinities for the membrane-bound receptors were measured at different ionic strengths and temperatures and compared with those determined on the receptor solubilised in the neutral detergent digitonin or the zwitterionic detergent, CHAPSO. 3. The range of measured affinity constants of a given antagonist for a specific subtype varied from 2 (atropine at M1 receptors) to 1000 (AF-DX 116 at M2 receptors). 4. As a consequence of these changes in affinity, which were dependent on the drug, the subtype and the experimental conditions, both the structure-binding relationships of a given subtype can be markedly changed as well as the selectivity of a drug for the different subtypes. For example it is possible to change the relative affinities of AF-DX 116 and gallamine at membrane-bound M1 receptors from 50:1 to 1:60. 5. Experimental conditions for the observation of high selectivity of pirenzepine, AF-DX 116, gallamine and hexahydrosiladiphenidol for the three subtypes are given. 6. When the receptors are removed from their membrane environment by solubilisation in detergent, antagonist affinities are changed but the subtypes still retain different structure-binding relationships. 7. In general, AF-DX 116 and the allosteric antagonist, gallamine, behave differently from the other antagonists, suggesting that they bind in different ways to muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
1561

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barlow R. B., Birdsall N. J., Hulme E. C. Temperature coefficients of affinity constants for the binding of antagonists to muscarinic receptors in the rat cerebral cortex. Br J Pharmacol. 1979 Aug;66(4):587–590. doi: 10.1111/j.1476-5381.1979.tb13698.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berrie C. P., Birdsall N. J., Hulme E. C., Keen M., Stockton J. M. Solubilization and characterization of guanine nucleotide-sensitive muscarinic agonist binding sites from rat myocardium. Br J Pharmacol. 1984 Aug;82(4):853–861. doi: 10.1111/j.1476-5381.1984.tb16482.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berrie C. P., Birdsall N. J., Hulme E. C., Keen M., Stockton J. M. Solubilization and characterization of high and low affinity pirenzepine binding sites from rat cerebral cortex. Br J Pharmacol. 1985 Jul;85(3):697–703. doi: 10.1111/j.1476-5381.1985.tb10566.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berstein G., Haga T., Ichiyama A. Effect of the lipid environment on the differential affinity of purified cerebral and atrial muscarinic acetylcholine receptors for pirenzepine. Mol Pharmacol. 1989 Oct;36(4):601–607. [PubMed] [Google Scholar]
  5. Birdsall N. J., Burgen A. S., Hulme E. C., Wells J. W. The effects of ions on the binding of agonists and antagonists to muscarinic receptors. Br J Pharmacol. 1979 Nov;67(3):371–377. doi: 10.1111/j.1476-5381.1979.tb08690.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Birdsall N. J., Chan S. C., Eveleigh P., Hulme E. C., Miller K. W. The modes of binding of ligands to cardiac muscarinic receptors. Trends Pharmacol Sci. 1989 Dec;Suppl:31–34. [PubMed] [Google Scholar]
  7. Birdsall N. J., Hulme E. C., Keen M., Pedder E. K., Poyner D., Stockton J. M., Wheatley M. Soluble and membrane-bound muscarinic acetylcholine receptors. Biochem Soc Symp. 1986;52:23–32. [PubMed] [Google Scholar]
  8. Birdsall N. J., Hulme E. C., Keen M. The binding of pirenzepine to digitonin-solubilized muscarinic acetylcholine receptors from the rat myocardium. Br J Pharmacol. 1986 Feb;87(2):307–316. doi: 10.1111/j.1476-5381.1986.tb10819.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Burgisser E., De Lean A., Lefkowitz R. J. Reciprocal modulation of agonist and antagonist binding to muscarinic cholinergic receptor by guanine nucleotide. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1732–1736. doi: 10.1073/pnas.79.6.1732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Curtis C. A., Wheatley M., Bansal S., Birdsall N. J., Eveleigh P., Pedder E. K., Poyner D., Hulme E. C. Propylbenzilylcholine mustard labels an acidic residue in transmembrane helix 3 of the muscarinic receptor. J Biol Chem. 1989 Jan 5;264(1):489–495. [PubMed] [Google Scholar]
  11. Eveleigh P., Hulme E. C., Schudt C., Birdsall N. J. The existence of stable enantiomers of telenzepine and their stereoselective interaction with muscarinic receptor subtypes. Mol Pharmacol. 1989 Apr;35(4):477–483. [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. Hulme E. C., Berrie C. P., Birdsall N. J., Burgen A. S. Two populations of binding sites for muscarinic antagonists in the rat heart. Eur J Pharmacol. 1981 Jul 17;73(2-3):137–142. doi: 10.1016/0014-2999(81)90085-6. [DOI] [PubMed] [Google Scholar]
  15. Hulme E. C., Berrie C. P., Birdsall N. J., Jameson M., Stockton J. M. Regulation of muscarinic agonist binding by cations and guanine nucleotides. Eur J Pharmacol. 1983 Oct 14;94(1-2):59–72. doi: 10.1016/0014-2999(83)90442-9. [DOI] [PubMed] [Google Scholar]
  16. Hulme E. C., Birdsall N. J., Buckley N. J. Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol. 1990;30:633–673. doi: 10.1146/annurev.pa.30.040190.003221. [DOI] [PubMed] [Google Scholar]
  17. Hulme E. C., Birdsall N. J., Burgen A. S., Mehta P. The binding of antagonists to brain muscarinic receptors. Mol Pharmacol. 1978 Sep;14(5):737–750. [PubMed] [Google Scholar]
  18. Kurtenbach E., Curtis C. A., Pedder E. K., Aitken A., Harris A. C., Hulme E. C. Muscarinic acetylcholine receptors. Peptide sequencing identifies residues involved in antagonist binding and disulfide bond formation. J Biol Chem. 1990 Aug 15;265(23):13702–13708. [PubMed] [Google Scholar]
  19. Poyner D. R., Birdsall N. J., Curtis C., Eveleigh P., Hulme E. C., Pedder E. K., Wheatley M. Binding and hydrodynamic properties of muscarinic receptor subtypes solubilized in 3-(3-cholamidopropyl)dimethylammonio-2-hydroxy-1-propanesulfonate. Mol Pharmacol. 1989 Sep;36(3):420–429. [PubMed] [Google Scholar]
  20. Roffel A. F., Elzinga C. R., Meurs H., Zaagsma J. Allosteric interactions of three muscarine antagonists at bovine tracheal smooth muscle and cardiac M2 receptors. Eur J Pharmacol. 1989 Mar 7;172(1):61–70. doi: 10.1016/0922-4106(89)90045-x. [DOI] [PubMed] [Google Scholar]
  21. Schudt C., Boer R., Eltze M., Riedel R., Grundler G., Birdsall N. J. The affinity, selectivity and biological activity of telenzepine enantiomers. Eur J Pharmacol. 1989 Jun 8;165(1):87–96. doi: 10.1016/0014-2999(89)90773-5. [DOI] [PubMed] [Google Scholar]
  22. 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]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES