title: [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]-trimethylammonium (McN-A-343)-related compounds. Effect of the butynyl chain inclusion into an aromatic unit on the potency for muscarinic receptors.
abstract: A series of derivatives of the known M1 selective muscarinic receptor agonist McN-A-343 (1) was designed with the aim of investigating the effects of structural variations on both the butynyl chain and the phenyl ring of 1. The butynyl chain was replaced with an aromatic spacer, and the effects of such a modification on the stereoelectronic properties of the molecules were theoretically studied and considered compatible with muscarinic receptor affinity. Substituents on the phenyl ring of 1 were selected so as to vary their electronic and hydrophobic properties. This design strategy did not produce muscarinic M1 receptor agonists more potent than the prototype 1, even if some analogues displayed functional selectivity for different muscarinic receptor subtypes. Compounds 3 and 7 were selective agonists towards muscarinic M3 receptors, while compounds 14, 16 and 18 were selective muscarinic M2 receptor agonists. The most interesting derivative was 8, a full agonist at muscarinic M3 receptors devoid of activity at both muscarinic M1 and M2 subtypes. The pharmacological profile of the series was further characterized by studying the anticholinesterase and miotic activities of some representative compounds. Compounds 3-8 turned out to be weak acetylcholinesterase inhibitors, while derivatives 4, 6, 8 and 11 were able to significantly reduce the pupillary diameter in rabbit, indicating 8 as an effective miotic agent.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Tumiatti
authors.forename: P
authors.initials: P
authors.lastname: Angeli
authors.forename: V
authors.initials: V
authors.lastname: Andrisano
authors.forename: M L
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: A
authors.initials: A
authors.lastname: Cavalli
authors.forename: G
authors.initials: G
authors.lastname: Marucci
authors.forename: A
authors.initials: A
authors.lastname: Minarini
authors.forename: M
authors.initials: M
authors.lastname: Recanatini
authors.forename: M
authors.initials: M
authors.lastname: Rosini
authors.forename: C
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D015877:Miosis; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D018721:Muscarinic Agonists; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride