Dioxane and oxathiane nuclei: Suitable substructures for muscarinic agonists

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 2; pp. 886 - 896
• Main Authors: Piergentili, Alessandro, Quaglia, Wilma, Giannella, Mario, Bello, Fabio Del, Bruni, Bruno, Buccioni, Michela, Carrieri, Antonio, Ciattini, Samuele
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.01.2007
• Subjects: 1,4-Dioxane nucleus; 1,4-Oxathiane nucleus; Animals; Crystallography, X-Ray; Dioxanes - chemistry; Dose-Response Relationship, Drug; Guinea Pigs; Heart Atria - drug effects; Heterocyclic Compounds, 1-Ring - chemical synthesis; Heterocyclic Compounds, 1-Ring - pharmacology; Ileum - drug effects; Indicators and Reagents; Isomerism; Lung - drug effects; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Muscarinic agonists; Muscarinic Agonists - chemical synthesis; Muscarinic Agonists - pharmacology; Muscle, Smooth - drug effects; Rabbits; Receptor, Muscarinic M1 - agonists; Receptor, Muscarinic M2 - agonists; Receptor, Muscarinic M3 - agonists; Receptor, Muscarinic M4 - agonists; Structure-Activity Relationship; Subtype selectivity; Vas Deferens - drug effects; 1,4-Oxathiane nucleus; Muscarinic agonists; Subtype selectivity; 1,4-Dioxane nucleus
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.10.040

Muscarinic agonists, bearing 1,4-dioxane and 1,4-oxathiane nuclei, were synthesized and tested to evaluate their potency at M 1–M 4 muscarinic receptor subtypes. The stereochemical relationship between the 2-side chain and the 6-methyl group plays an important role in drug–receptor interaction, since the cis isomers are more potent than the corresponding trans isomers. However, the latter are able to discriminate between the muscarinic receptor subtypes. Among them compound 5b proves particularly interesting, since it selectively activates the ileal M 3 receptor subtype and is devoid of agonist activity at the others.