title: Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes.
abstract: The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Biocentre Niederursel, University of Frankfurt, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Moser
authors.forename: C
authors.initials: C
authors.lastname: Gubitz
authors.forename: M
authors.initials: M
authors.lastname: Galvan
authors.forename: A
authors.initials: A
authors.lastname: Immel-Sehr
authors.forename: G
authors.initials: G
authors.lastname: Lambrecht
authors.forename: E
authors.initials: E
authors.lastname: Mutshcler
mesh_terms: D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017783:Superior Cervical Ganglion / Q000187:drug effects
chemical_list: D008024:Ligands; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C015000:arecaidine esters; D001115:Arecoline