Dioxane and oxathiane nuclei: suitable substructures for muscarinic agonists.
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.
Piergentili
Alessandro
A
Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, Via S. Agostino, 1, 62032 Camerino, Italy. alessandro.piergentili@unicam.it
Quaglia
Wilma
W
Giannella
Mario
M
Del Bello
Fabio
F
Bruni
Bruno
B
Buccioni
Michela
M
Carrieri
Antonio
A
Ciattini
Samuele
S
D000818:Animals; D018360:Crystallography, X-Ray; D004146:Dioxanes / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D007202:Indicators and Reagents; D007536:Isomerism; D008168:Lung / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects; D011817:Rabbits; D043643:Receptor, Muscarinic M1 / Q000819:agonists; D043585:Receptor, Muscarinic M2 / Q000819:agonists; D043587:Receptor, Muscarinic M3 / Q000819:agonists; D043588:Receptor, Muscarinic M4 / Q000819:agonists; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D004146:Dioxanes; D006573:Heterocyclic Compounds, 1-Ring; D007202:Indicators and Reagents; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; C517814:oxathiane