Advertisement

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 338, Issue 5, pp 476–483 | Cite as

The relative potencies of cholinomimetics and muscarinic antagonists on the rat iris in vivo: effects of pH on potency of pirenzepine and telenzepine

  • J. J. Hagan
  • B. van der Heijden
  • C. L. E. Broekkamp
Article

Summary

The effects of cholinomimetics and muscarinic antagonists were compared following topical administration to the eyes of anaesthetized rats. For tests with cholinomimetics, clonidine (0.3 mg/kg) was used to induce mydriasis via central inhibition of parasympathetic tone. Full, dose-dependent miosis was induced by acetylcholinesterase inhibitors [physostigmine > neostigmine > tetrahydroaminoacridine (THA)] and by membrane channel blockers (4-aminopyridine > 3,4-diaminopyridine). Oxotremorine was the most potent direct agonist tested [oxotremorine > arecaidine propargylester (APE) > arecolne > carbachol > ethoxyethyltrimethyl-ammonium iodide (EOE) > RS 86]. Some putative M1 selective agonists were weakly active or behaved as partial agonists (pilocarpine > AH6405 > Mc-A-343 > isoarecoline). Of the antagonists, compared in non-clonidine treated rats, scopolamine hydrochloride was the most potent. Of the receptor selective antagonists the M2 (ileal) selective compounds hexahydrosiladifenidol and 4-DAMP were more potent than either M1 selective (pirenzepine, telenzepine) or M2 (atrial) selective (AF DX 116) drugs. These data tentatively suggest the involvement of an M2 (ileal) type muscarinic receptor. Potency was lower for quaternary structures, probably due to impaired corneal penetration. The potency of pirenzepine and telenzepine was increased 60-fold at low pH following topical administration. Acid induced corneal damage does not appear to account for this potency shift as the effects of scopolamine and several agonists (oxotremorine, pilocarpine and McN-A-343) were not substantially altered by acid media. For pirenzepine the potency shift appears to be related to protonation of the second amino group (N1) in the piperazine tail (pKa = 2.05). Intraocular injections suggest that diprotonation facilitates penetration through the cornea. This anomalous behaviour of pirenzepine may contribute to its potency in gastric acid inhibition where the acid environment of the stomach would favour the diprotonated state and therefore penetration through the epithelium.

Key words

Mydriasis Muscarinic antagonist Cholinomimetics M1/M2 Receptors Pirenzepine pH 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anthony BL, Aronstam RS (1986) High-affinity agonist binding to rat brain stem muscarinic receptors is eliminated by low pH. Neurosci Lett 69:84–88CrossRefGoogle Scholar
  2. Barlow RB, Berry KJ, Glenton PAM, Nikolau NM, Soh KS (1976) A comparison of affinity constants for muscarinic-sensitive acetylcholine receptors in guinea-pig atrial pace maker cells at 29°C and in ileum at 29°C and 37°C. Br J Pharmacol 58:613–620CrossRefGoogle Scholar
  3. Barlow RB, Burston KN, Vis A (1980) Three types of muscarinic receptors? Br J Pharmacol 68 (Suppl):141–142Google Scholar
  4. Barlow RB, Chan M (1982) The effects of pH on the affinity of pirenzepine for muscarinic receptors in the guinea-pig ileum and rat fundus strip. Br J Pharmacol 77:559–563CrossRefGoogle Scholar
  5. Barlow RB, Weston-Smith P (1985) The relative potencies of some agonists at M2 muscarinic receptors in guinea-pig ileum, atria and bronchi. Br J Pharmacol 85:437–440CrossRefGoogle Scholar
  6. Barlow RB, Winter EA (1981) 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 72:657–664CrossRefGoogle Scholar
  7. Baudiere B, Monferini E, Giraldo H, Ladinski H, Bali JP (1987) Characterization of the muscarinic receptor subtype in isolated gastric fundic cells of the rabbit. Biochem Pharmacol 36: 2957–2961CrossRefGoogle Scholar
  8. Berridge TL, Gadie B, Roach AG, Tulloch IF (1983) α2-Adrenoceptor agonists induce mydriasis in the rat by an action within the central nervous system. Br J Pharmacol 78:507–515CrossRefGoogle Scholar
  9. Black JW, Shankley NP (1985) Pharmacological analysis of muscarinic receptors coupled to oxyntic cell secretion in the mouse stomach. Br J Pharmacol 86:601–607CrossRefGoogle Scholar
  10. Caulfield MP, Stubley JK (1982) Pilocarpine selectively stimulates muscarinic receptors in rat sympathetic ganglia. Br J Pharmacol 76 (Suppl):216PGoogle Scholar
  11. Davidesko D, De Jonge A, Doods NH, van Charldorp KJ, Mathy MJ, van Zwieten PA (1986) In vivo potencies of selective muscarinic antagonists support the subdivision of M-receptors into M1, M2 and M3 subtypes. Br J Pharmacol 90, suppl. 160PGoogle Scholar
  12. Eberlein WG, Trummlitz G, Engel WW, Schmidt G, Pelzer H, Mayer N (1987) Tricyclic compounds as selective antimuscarinics I. Structural requirements for selectivity toward the muscarinic acetylcholine receptor in a series of pirenzepine and imipramine analogues. J Med Chem 30:1378–1382CrossRefGoogle Scholar
  13. Eglen RM, Whiting RL (1986) Differential affinities of muscarinic antagonists at ileal and atrial receptors. Br J Pharmacol 87 (Suppl):33PGoogle Scholar
  14. Eglen RM, Whiting RL (1987) Competitive and non-competitive antagonism exhibited by ‘selective’ antagonists at atrial and ileal muscarinic receptor subtypes. Br J Pharmacol 90:701–707CrossRefGoogle Scholar
  15. Eltze M, Gonne S, Riedel R, Schlotke B, Schudt C, Simon WA (1985) Pharmacological evidence for selective inhibition of gastric acid secretion by telenzepine, a new antimuscarinic drug. Eur J Pharmacol 112:211–224CrossRefGoogle Scholar
  16. Franko BV, Ward JW, Alphin RS (1963) Pharmacological studies of N-benzyl-3-pyrrolidyl acetate methobromide (AHR602), a ganglionic stimulating agent. J Pharmacol Exp Ther 139:25–30Google Scholar
  17. Fuder H, Kilbinger H, Muller H (1985) Organ selectivity of hexahydrosiladifenidol in blocking pre- and post-junctional muscarinic receptors studied in guinea-pig ileum and rat heart. Eur J Pharmacol 113:125–127CrossRefGoogle Scholar
  18. Giachetti A, Micheletti R, Montagna E (1986) Cardioselective profile of AF-DX 116, a muscarinic M2 receptor antagonist. Life Sci 38:1663–1672CrossRefGoogle Scholar
  19. Gower AJ, Broekkamp CLE, Rijk HW, Van Delft AML (1988) Pharmacological evaluation of in vivo tests for α2-adrenoceptor blockade in the central nervous system and the effects of the enantiomers of mianserin and its Aza-analog Org 3770. Arch Int Pharmacodyn 291:185–201PubMedGoogle Scholar
  20. Grass GM, Robinson JR (1988a) Mechanisms of corneal drug penetration. I. In vivo and in vitro kinetics. J Pharmaceutical Sci 77:3–14CrossRefGoogle Scholar
  21. Grass GM, Robinson JR (1988b) Mechanisms of corneal drug penetration. II. Ultrastructural analysis of potential pathways for drug movement. J Pharmaceutical Sci 77:15–23CrossRefGoogle Scholar
  22. Grass GM, Cooper ER, Robinson JR (1988c) Mechanisms of corneal drug penetration. III. Modelling of molecular transport. J. Pharmaceutical Sci 77:24–26CrossRefGoogle Scholar
  23. Hammer R, Berrie CP, Birdsall NJM, Burgen ASV, Hulme EC (1980) Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283:90–92CrossRefGoogle Scholar
  24. Hammer R, Giachetti A (1982) Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization. Life Sci 31:2991–2998CrossRefGoogle Scholar
  25. Heilbronn E (1961) Inhibition of cholinesterase by tetrahydroaminoacridine. Acta Chem Scand 15:1386CrossRefGoogle Scholar
  26. Hey JA, Gherezghiher T, Koss MC (1985) Studies on the mechanism of clonidine-induced mydriasis in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 328:258–263CrossRefGoogle Scholar
  27. Koss MC (1986) Papillary dilation as an index of central nervous system α2-adrenoceptor activation. J Pharmacol Meth 15:1–9CrossRefGoogle Scholar
  28. Lambrecht G, Moser U, Gmelin G, Tacke R, Mutschler E (1987) Heterogeneity in muscarinic receptors: Evidence from pharmacological and electrophysiological studies with selective antagonists. In: Cohen S, Sokolovsky M (eds) Muscarinic cholinergic mechanisms. Freund Publishing House, London Tel-Aviv, pp 243–245Google Scholar
  29. Loewenfeld IE (1958) Mechanisms of reflex dilation of the pupil. Documenta Opthalmologica 12:185–448CrossRefGoogle Scholar
  30. Marshall RJ (1970) A new muscarinic agent: 1,4,5,6-tetrahydro-5-phenoxy pyrimidine (AH6405). Br J Pharmacol 39 (Suppl):191Google Scholar
  31. Molgo J, Lundh H, Thesleff S (1980) Potency of 3,4-diaminopyridine and 4-aminopyridine on mammalian neuromuscular transmission and the effect of pH changes. Eur J Pharmacol 61:25–34CrossRefGoogle Scholar
  32. Roszkowski AP (1961) An unusual type of sympathetic ganglion stimulant. J Pharmacol Exp Ther 132:156–170PubMedGoogle Scholar
  33. Schauf CL, Sattin A (1987) Tetrahydroaminoacridine blocks potassium channels and inhibits sodium inactivation in myxicola. J Pharmacol Exp Ther 243:609–613PubMedGoogle Scholar
  34. Schudt C, Auriga C, Kinder B (1987) [3H]-Telenzepine — anew M1-selective antimuscarinic ligand. Naunyn-Schmiedeberg's Arch Pharmacol Suppl to Vol 335:310Google Scholar
  35. Sieg JW, Robinson JR (1977) Vehicle effects on ocular drug availability. II. Evaluation of pilocarpine. J Pharmaceut Sci 66: 1222–1228CrossRefGoogle Scholar
  36. Stevens DR, Cotman CW (1987) Excitatory actions of tetrahydro-9-aminoacridine (THA) on hippocampal pyramidal neurons. Neurosci Lett 79:301–305CrossRefGoogle Scholar
  37. Thesleff S (1980) Aminopyridines and synaptic transmission. Neuroscience 5:1413–1419CrossRefGoogle Scholar
  38. Tonnaer JADM, Van Vugt MA, De Boer Th, De Graaf JS (1987) Differential interaction of muscarinic drugs with binding sites of [3H]pirenzepine and [3H]quinuclidinyl benzilate in rat brain tissue. Life Sci 40:1981–1987CrossRefGoogle Scholar
  39. Warwick R (1954) The ocular parasympathetic nerve supply and its mesencephalic sources. J Anat 88:71–93PubMedPubMedCentralGoogle Scholar
  40. Wess J, Lambrecht G, Moser U, Mutschler E (1987) Stimulation of ganglionic muscarinic M1 receptors by a series of tertiary arecaidine and isoarecaidine esters in the pithed rat. Eur J Pharmacol 134:61–67CrossRefGoogle Scholar
  41. Yeh JZ, Oxford GS, Wu CH, Narahashi T (1976) Dynamics of aminopyridine block of potassium channels in squid axon membrane. J Gen Physiol 68:519–535CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • J. J. Hagan
    • 1
  • B. van der Heijden
    • 1
  • C. L. E. Broekkamp
    • 1
  1. 1.CNS Pharmacology LabsOrganon International B. V.BH OssThe Netherlands

Personalised recommendations