title: New functionally selective muscarinic agonists.
abstract: The muscarinic pharmacology of two novel agonists related to McN-A-343, 4-F-PyMcN and 4-F-PyMcN+, has been studied by the use of pharmacological and radioligand binding techniques. Both compounds were potent agonists at M1 receptors in rabbit vas deferens (pEC50 = 6.24 and 6.96) and rat duodenum (pEC50 = 5.47 and 6.38), but very weak partial agonists or competitive antagonists at guinea-pig cardiac M2 and ileal M3 receptors. There was no receptor reserve for 4-F-PyMcN in rabbit vas deferens, for which the potency (pEC50 = 6.24) and apparent affinity (pKA = 5.99 and 6.21) were similar. 4-F-PyMcN+ showed only limited binding selectivity between four muscarinic receptor binding assays with apparent affinity constants (pKi) of 5.8, 5.2, 5.6 and 5.7 for M1, M2, M3 and M4 muscarinic receptor subtypes. The two novel functionally M1-selective agonists may provide useful tools with which to study muscarinic receptor mechanisms. The non-quaternary compound, 4-F-PyMcN, might become a starting point for the development of drugs that selectively affect M1 receptors involved in central cholinergic function.
authors.affiliation: Department of Pharmacology, University of Frankfurt, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Lambrecht
authors.forename: U
authors.initials: U
authors.lastname: Moser
authors.forename: U
authors.initials: U
authors.lastname: Grimm
authors.forename: O
authors.initials: O
authors.lastname: Pfaff
authors.forename: U
authors.initials: U
authors.lastname: Hermanni
authors.forename: C
authors.initials: C
authors.lastname: Hildebrandt
authors.forename: M
authors.initials: M
authors.lastname: Waelbroeck
authors.forename: J
authors.initials: J
authors.lastname: Christophe
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000031:analogs & derivatives; D000818:Animals; D004386:Duodenum / Q000378:metabolism; D006168:Guinea Pigs; D006325:Heart Atria / Q000378:metabolism; D008297:Male; D010277:Parasympathomimetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects*
chemical_list: C079886:1-(4-((4-fluorophenylcarbamoyl)oxy)butynyl)pyrrolidinium; D010277:Parasympathomimetics; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; C079887:1-methyl-1-(4-((4-fluorophenylcarbamoyl)oxy)butynyl)pyrrolidinium; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride