Home LiteratureArticle Details
PMID: 3244389 Published · ppublish English Journal Article

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

Naunyn-Schmiedeberg's archives of pharmacology ·Vol. 338 ·No. 5 ·1988-11-00 ·Pages 476-83

Hagan JJ, van der Heijden B, Broekkamp CL

Abstract

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 greater than neostigmine greater than tetrahydroaminoacridine (THA)] and by membrane channel blockers (4-aminopyridine greater than 3,4-diaminopyridine). Oxotremorine was the most potent direct agonist tested [oxotremorine greater than arecaidine propargylester (APE) greater than arecoline greater than carbachol greater than ethoxyethyltrimethyl-ammonium iodide (EOE) greater than RS 86]. Some putative M1 selective agonists were weakly active or behaved as partial agonists (pilocarpine greater than AH6405 greater than Mc-A-343 greater than 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 McNA-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).(ABSTRACT TRUNCATED AT 250 WORDS)

MeSH Terms
Animals Dose-Response Relationship, Drug Hydrogen-Ion Concentration Iris/drug effects,physiology Male Muscarine/antagonists & inhibitors Ophthalmic Solutions Parasympathomimetics/administration & dosage,pharmacology Pirenzepine/administration & dosage,analogs & derivatives,pharmacology Pupil/drug effects Rats Rats, Inbred Strains Receptors, Muscarinic/drug effects,metabolism
Chemicals
Ophthalmic Solutions Parasympathomimetics Receptors, Muscarinic telenzepine Pirenzepine Muscarine
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Hagan J J
CNS Pharmacology Labs, Organon International B.V., Oss. The Netherlands.
van der Heijden B
Broekkamp C L
References (34)
34 references, click to expand
  1. Mechanisms of corneal drug penetration. III: Modeling of molecular transport.
    J Pharm Sci. 1988 Jan;77(1):24-6 PMID: 3346819
  2. Mechanisms of corneal drug penetration. II: Ultrastructural analysis of potential pathways for drug movement.
    J Pharm Sci. 1988 Jan;77(1):15-23 PMID: 3346818
  3. Pirenzepine distinguishes between different subclasses of muscarinic receptors.
    Nature. 1980 Jan 3;283(5742):90-2 PMID: 7350532
  4. Tricyclic compounds as selective antimuscarinics. 1. Structural requirements for selectivity toward the muscarinic acetylcholine receptor in a series of pirenzepine and imipramine analogues.
    J Med Chem. 1987 Aug;30(8):1378-82 PMID: 3039133
  5. Pharmacological evidence for selective inhibition of gastric acid secretion by telenzepine, a new antimuscarinic drug.
    Eur J Pharmacol. 1985 Jun 7;112(2):211-24 PMID: 4029260
  6. Aminopyridines and synaptic transmission.
    Neuroscience. 1980;5(8):1413-9 PMID: 6250099
  7. Dynamics of aminopyridine block of potassium channels in squid axon membrane.
    J Gen Physiol. 1976 Nov;68(5):519-35 PMID: 993770
  8. Vehicle effects on ocular drug bioavailability II: Evaluation of pilocarpine.
    J Pharm Sci. 1977 Sep;66(9):1222-8 PMID: 20491
  9. The relative potencies of some agonists at M2 muscarinic receptors in guinea-pig ileum, atria and bronchi.
    Br J Pharmacol. 1985 Jun;85(2):437-40 PMID: 3896364
  10. Pupillary dilation as an index of central nervous system alpha 2-adrenoceptor activation.
    J Pharmacol Methods. 1986 Feb;15(1):1-19 PMID: 2869190
  11. Excitatory actions of tetrahydro-9-aminoacridine (THA) on hippocampal pyramidal neurons.
    Neurosci Lett. 1987 Aug 31;79(3):301-5 PMID: 3658222
  12. Competitive and non-competitive antagonism exhibited by 'selective' antagonists at atrial and ileal muscarinic receptor subtypes.
    Br J Pharmacol. 1987 Apr;90(4):701-7 PMID: 3580704
  13. Pharmacological evaluation of in vivo tests for alpha 2-adrenoceptor blockade in the central nervous system and the effects of the enantiomers of mianserin and its aza-analog ORG 3770.
    Arch Int Pharmacodyn Ther. 1988 Jan-Feb;291:185-201 PMID: 2896489
  14. Pharmacological analysis of muscarinic receptors coupled to oxyntic cell secretion in the mouse stomach.
    Br J Pharmacol. 1985 Nov;86(3):601-7 PMID: 2866004
  15. Organ selectivity of hexahydrosiladifenidol in blocking pre- and postjunctional muscarinic receptors studied in guinea-pig ileum and rat heart.
    Eur J Pharmacol. 1985 Jul 11;113(1):125-7 PMID: 3840090
  16. Tetrahydroaminoacridine blocks potassium channels and inhibits sodium inactivation in Myxicola.
    J Pharmacol Exp Ther. 1987 Nov;243(2):609-13 PMID: 2445954
  17. Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization.
    Life Sci. 1982 Dec 27;31(26):2991-8 PMID: 6897666
  18. High-affinity agonist binding to rat brainstem muscarinic receptors is eliminated by low pH.
    Neurosci Lett. 1986 Aug 15;69(1):84-8 PMID: 3748469
  19. 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):559-63 PMID: 6897199
  20. An unusual type of sympathetic ganglionic stimulant.
    J Pharmacol Exp Ther. 1961 May;132:156-70 PMID: 13743787
  21. Characterization of the muscarinic receptor subtype in isolated gastric fundic cells of the rabbit.
    Biochem Pharmacol. 1987 Sep 15;36(18):2957-61 PMID: 3632720
  22. Three types of muscarinic receptors? [proceedings].
    Br J Pharmacol. 1980 Jan;68(1):141P-142P PMID: 7357156
  23. The ocular parasympathetic nerve supply and its mesencephalic sources.
    J Anat. 1954 Jan;88(1):71-93 PMID: 13129172
  24. 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):613-20 PMID: 1000135
  25. 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):657-64 PMID: 7284683
  26. Differential interactions of muscarinic drugs with binding sites of [3H]pirenzepine and [3H]quinuclidinyl benzilate in rat brain tissue.
    Life Sci. 1987 May 18;40(20):1981-7 PMID: 3573989
  27. Mechanisms of reflex dilatation of the pupil; historical review and experimental analysis.
    Doc Ophthalmol. 1958;12:185-448 PMID: 13609524
  28. Potency of 3,4-diaminopyridine and 4-aminopyridine on mammalian neuromuscular transmission and the effect of pH changes.
    Eur J Pharmacol. 1980 Jan 11;61(1):25-34 PMID: 6101553
  29. alpha 2-Adrenoceptor agonists induced mydriasis in the rat by an action within the central nervous system.
    Br J Pharmacol. 1983 Mar;78(3):507-15 PMID: 6132641
  30. Stimulation of ganglionic muscarinic M1 receptors by a series of tertiary arecaidine and isoarecaidine esters in the pithed rat.
    Eur J Pharmacol. 1987 Jan 28;134(1):61-7 PMID: 3556399
  31. Studies on the mechanism of clonidine-induced mydriasis in the rat.
    Naunyn Schmiedebergs Arch Pharmacol. 1985 Jan;328(3):258-63 PMID: 2984585
  32. Cardioselective profile of AF-DX 116, a muscarine M2 receptor antagonist.
    Life Sci. 1986 May 5;38(18):1663-72 PMID: 3754611
  33. A new muscarinic agent: 1,4,5,6-tetrahydro-5-phenoxypyrimidine (AH 6405).
    Br J Pharmacol. 1970 May;39(1):191P-192P PMID: 5420095
  34. Mechanisms of corneal drug penetration. I: In vivo and in vitro kinetics.
    J Pharm Sci. 1988 Jan;77(1):3-14 PMID: 3126290
Article Info
Journal
Naunyn-Schmiedeberg's archives of pharmacology
Abbr.
Naunyn Schmiedebergs Arch Pharmacol
ISSN
0028-1298
DOI
10.1007/BF00179317
Published
1988-11-00
Pages
476-83
Language
English
Region
Germany
NLM ID
0326264
Subset
IM
External Links
PubMed source DOI: 10.1007/BF00179317 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2