Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1981 Apr;72(4):657–664. doi: 10.1111/j.1476-5381.1981.tb09146.x

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.

R B Barlow, E A Winter
PMCID: PMC2071641  PMID: 7284683

Abstract

1. At 37 degrees C in 0.1 M NaCl the pKa of hyoscine (10 mM) is 7.53; the non-protonated form has about one-tenth of the affinity (log K = 8.58) of the protonated form (log K = 9.58) for muscarine-sensitive receptors of the guinea-pig ileum at 37 degrees C. 2. In the same conditions the pKa of hyoscine N-oxide is 5.78 and the non-protonated form is inactive on the ileum whereas the protonated form is highly active with log K estimated to be 9.9, at least as active as hyoscine methobromide (log K = 9.85). 3. Hyoscine methobromide appears to occupy less space in water than atropine methobromide; hyoscine hydrochloride occupies less space than hyoscyamine hydrochloride: the non-protonated forms are slightly bigger. Hyoscine N-oxide hydrobromide is slightly smaller than hyoscine methobromide but the removal of the proton is accompanied by a reduction in volume, such as is seen with other zwitterions. 4. These differences in volume indicated a reduction in entropy on solution which may allow a greater increase in entropy on binding to receptors and hence greater affinity. The higher activity of hyoscine itself could also be due to the presence of the N-methyl group in the axial position, rather than equatorial as in hyoscyamine or atropine. 5. The different position of the N-methyl group may partly explain why the pKa of hyoscine is 2 units lower than that of hyoscyamine or atropine. It is also probable that the unionized form of hyoscine is stabilized by hydration. 6. Although hyoscine N-oxide is only weakly active at pH 7.6, it is present in a highly active form in the acid environment of the stomach and so might be expected to act selectively at this site.

Full text

PDF
657

Selected References

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

  1. Armstrong J., Barlow R. B. The ionization of phenolic amines, including apomorphine, dopamine and catecholamines and an assessment of zwitterion constants. Br J Pharmacol. 1976 Aug;57(4):501–516. doi: 10.1111/j.1476-5381.1976.tb10377.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barlow R. B., Burston K. N. A comparison of cinobufotenine (the quaternary derivative of 5-HT) and some related compounds with coryneine (the quaternary derivative of dopamine) on the frog rectus, guinea-pig ileum and rat fundus strip preparations. Br J Pharmacol. 1980 Aug;69(4):597–600. doi: 10.1111/j.1476-5381.1980.tb07909.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barlow R. B., Burston K. N. Temperature coefficients of affinity and entropies of adsorption from enantiomeric pairs of compounds acting at muscarinic receptors in the guinea-pig ileum. Br J Pharmacol. 1979 Aug;66(4):581–585. doi: 10.1111/j.1476-5381.1979.tb13697.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barlow R. B., Burston K. N. The ionization of 5-hydroxytryptamine and related compounds and an appraisal of methods for the estimation of zwitterion constants. Br J Pharmacol. 1980 Aug;69(4):587–595. doi: 10.1111/j.1476-5381.1980.tb07908.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barlow R. B., Franks F. M. A comparison of phenylalkyl- and phenoxyalkyl- trimethylammonium and triethylammonium salts; their apparent molal volumes at infinite dilution and effects on the frog rectus and guinea-pig ileum preparations. Br J Pharmacol. 1973 Nov;49(3):480–489. doi: 10.1111/j.1476-5381.1973.tb17258.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barlow R. B., Franks F. M., Pearson J. D. Studies on the stereospecificity of closely related compounds which block postganglionic acetylcholine receptors in the guinea-pig ileum. J Med Chem. 1973 May;16(5):439–446. doi: 10.1021/jm00263a003. [DOI] [PubMed] [Google Scholar]
  7. Barlow R. B., Harrison M., Ison R. R., Pearson J. D. Epimeric forms of quaternary derivatives of atropine. J Med Chem. 1973 May;16(5):564–566. doi: 10.1021/jm00263a037. [DOI] [PubMed] [Google Scholar]
  8. Barlow R. B., Ramtoola S. The size of the hydroxyl group and its contribution to the affinity of atropine for muscarine-sensitive acetylcholine receptors. Br J Pharmacol. 1980;71(1):31–34. doi: 10.1111/j.1476-5381.1980.tb10905.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Barlow R. B. The size of hydroxyl groups in solution and the changes in size associated with the ionization of phenolic, carboxylic and amino groups in phenolic quaternary ammonium salts, nicotine and some amino acids: possible implications for drug-water and drug-receptor interactions. Br J Pharmacol. 1980;71(1):17–30. doi: 10.1111/j.1476-5381.1980.tb10904.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Cannon J. G., Smith R. V., Fischer G. A. Amine oxide analogs of certain cholinergic agents. J Med Chem. 1971 Jan;14(1):66–68. doi: 10.1021/jm00283a021. [DOI] [PubMed] [Google Scholar]
  12. Darko L. L., Cannon J. G., Long J. P., Burks T. F. Synthesis and cholinergic effects of certain n-methoxylated quaternary compounds. J Med Chem. 1965 Nov;8(6):841–844. doi: 10.1021/jm00330a024. [DOI] [PubMed] [Google Scholar]
  13. Pauling P. J., Petcher T. J. Interaction of atropine with the muscarinic receptor. Nature. 1970 Nov 14;228(5272):673–674. doi: 10.1038/228673a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES