title: The relative potencies of cholinomimetics and muscarinic antagonists on the rat iris in vivo: effects of pH on potency of pirenzepine and telenzepine.
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)
authors.affiliation: CNS Pharmacology Labs, Organon International B.V., Oss. The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: B
authors.initials: B
authors.lastname: van der Heijden
authors.forename: C L
authors.initials: CL
authors.lastname: Broekkamp
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007498:Iris / Q000187:drug effects / Q000502:physiology; D008297:Male; D009116:Muscarine / Q000037:antagonists & inhibitors*; D009883:Ophthalmic Solutions; D010277:Parasympathomimetics / Q000008:administration & dosage / Q000494:pharmacology*; D010890:Pirenzepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011680:Pupil / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism
chemical_list: D009883:Ophthalmic Solutions; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; C046338:telenzepine; D010890:Pirenzepine; D009116:Muscarine