Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1992 Aug;106(4):819–822. doi: 10.1111/j.1476-5381.1992.tb14418.x

The contribution of charge to affinity at functional (M3) muscarinic receptors in guinea-pig ileum assessed from the effects of the carbon analogue of 4-DAMP methiodide.

R B Barlow 1, S Bond 1, D W Holdup 1, J A Howard 1, D S McQueen 1, A Paterson 1, M A Veale 1
PMCID: PMC1907653  PMID: 1393281

Abstract

1. 4-Diphenylacetoxy-1:1-dimethyl cyclohexane (carbo-4-DAMP) is the carbon analogue of 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methiodide. The compounds differ only in that the quaternary nitrogen atom in 4-DAMP methiodide is replaced by a quaternary carbon atom, which is uncharged. 2. Carbo-4-DAMP appears to act competitively at functional (M3) muscarinic receptors in guinea-pig ileum. Estimates of log affinity constant are 6.0 at 30 degrees C and 5.9 at 37 degrees C, i.e. the compound has 0.1% of the affinity of 4-DAMP methobromide. 3. The absence of charge makes little difference to the conformation as determined by X-ray crystallography. The bond lengths and angles are very similar, though the bonds in the cyclohexane ring of carbo-4-DAMP are consistently slightly longer than those in the piperidinium ring of 4-DAMP methiodide, and the presence of the charge slightly reduces the space between molecules. 4. The difference between the affinities of 4-DAMP methobromide and carbo-4-DAMP indicates that the contribution of coulombic forces to the binding between 4-DAMP methiodide and muscarinic (M3) receptors is at least 17 kJ mol-1 (4.1 kcal mol-1) at 37 degrees C. How much this is an underestimate depends upon how much hydrophobic binding is greater with the uncharged compound.

Full text

PDF
819

Selected References

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

  1. Abramson F. B., Barlow R. B., Mustafa M. G., Stephenson R. P. Relationships between chemical structure and affinity for acetylcholine receptors. Br J Pharmacol. 1969 Sep;37(1):207–233. doi: 10.1111/j.1476-5381.1969.tb09539.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. BANISTER J., WHITTAKER V. P. Pharmacological activity of the carbon analogue of acetylcholine. Nature. 1951 Apr 14;167(4250):605–606. doi: 10.1038/167605b0. [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. Barlow R. B., Chan M. The effects of pH on the affinity of pirenzepine for muscarinic receptors in the guinea-pig ileum and rat fundus strip. Br J Pharmacol. 1982 Nov;77(3):559–563. doi: 10.1111/j.1476-5381.1982.tb09331.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barlow R. B., Johnson O. The X-ray crystal structure of 4-diphenylcarbamyl-N-methyl-piperidine methobromide (the carbamate analogue of 4-DAMP methiodide). Br J Pharmacol. 1989 Oct;98(2):425–428. doi: 10.1111/j.1476-5381.1989.tb12613.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barlow R. B., Shepherd M. K. A further search for selective antagonists at M2-muscarinic receptors. Br J Pharmacol. 1986 Dec;89(4):837–843. doi: 10.1111/j.1476-5381.1986.tb11189.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barlow R. B., Shepherd M. K. A search for selective antagonists at M2 muscarinic receptors. Br J Pharmacol. 1985 Jun;85(2):427–435. doi: 10.1111/j.1476-5381.1985.tb08878.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Barlow R. B., Shepherd M. K., Tydeman H., Veale M. A. The affinity of some acetylenic analogues of 4-DAMP methobromide for muscarinic receptors in guinea-pig ileum and atria. Br J Pharmacol. 1988 Jul;94(3):947–951. doi: 10.1111/j.1476-5381.1988.tb11608.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Barlow R. B., Tubby J. H. Actions of some esters of 3,3-dimethylbutan-1-ol (the carbon analogue of choline) on the guinea-pig ileum. Br J Pharmacol. 1974 May;51(1):95–100. doi: 10.1111/j.1476-5381.1974.tb09636.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Barlow R. B., Winter E. A. Affinities of the protonated and non-protonated forms of hyoscine and hyoscine N-oxide for muscarinic receptors of the guinea-pig ileum and a comparison of their size in solution with that of atropine. Br J Pharmacol. 1981 Apr;72(4):657–664. doi: 10.1111/j.1476-5381.1981.tb09146.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Candell L. M., Yun S. H., Tran L. L., Ehlert F. J. Differential coupling of subtypes of the muscarinic receptor to adenylate cyclase and phosphoinositide hydrolysis in the longitudinal muscle of the rat ileum. Mol Pharmacol. 1990 Nov;38(5):689–697. [PubMed] [Google Scholar]
  13. Ehlert F. J., Delen F. M. Influence of pH on the binding of scopolamine and N-methylscopolamine to muscarinic receptors in the corpus striatum and heart of rats. Mol Pharmacol. 1990 Jul;38(1):143–147. [PubMed] [Google Scholar]
  14. 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]
  15. PATON W. D., RANG H. P. THE UPTAKE OF ATROPINE AND RELATED DRUGS BY INTESTINAL SMOOTH MUSCLE OF THE GUINEA-PIG IN RELATION TO ACETYLCHOLINE RECEPTORS. Proc R Soc Lond B Biol Sci. 1965 Aug 24;163:1–44. doi: 10.1098/rspb.1965.0058. [DOI] [PubMed] [Google Scholar]

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

RESOURCES