Muscarinic subtypes profile modulation within a series of new antagonists, bridged bicyclic derivatives of 2,2-Diphenyl-[1,3]-dioxolan-4-ylmethyl-dimethylamine

• Published in: Bioorganic & medicinal chemistry 2003-09, Vol.11 (18), p.3901-3911
• Main Authors: Piergentili, Alessandro, Gentili, Francesco, Ghelfi, Francesca, Marucci, Gabriella, Pigini, Maria, Quaglia, Wilma, Giannella, Mario
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Cholinergic system; Dioxolanes - chemical synthesis; Dioxolanes - chemistry; Dioxolanes - pharmacology; Guinea Pigs; Hydrocarbons, Iodinated - chemistry; Ileum - drug effects; Ileum - metabolism; In Vitro Techniques; Male; Medical sciences; Muscarinic Antagonists - chemical synthesis; Muscarinic Antagonists - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oxalates - chemistry; Pharmacology. Drug treatments; Rabbits; Receptors, Muscarinic - classification; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - metabolism; Stereoisomerism; Structure-Activity Relationship; Vas Deferens - drug effects; Vas Deferens - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00431-0

A set of new muscarinic antagonists, bridged bicyclic derivatives of 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-dimethylamine ( 1), was synthesized and tested to evaluate their affinity and selectivity for M 1, M 2, M 3 and M 4 receptor subtypes. The conformational constraint of 1 in a bicyclic structure, and the variation in distance and stereochemistry of the active functions allowed us to modulate the selectivity of interaction with the M 1–M 3 receptor subtypes. The most interesting compound was ( cis, trans)-2-(2,2-diphenylethyl)-5-methyl-tetrahydro-[1,3]dioxolo[4,5- c]pyrrole oxalate ( 6), which is equipotent with Pirenzepine on rabbit vas deferens (M 1-putative) but shows a better selectivity profile. The trans stereoisomer 6 ( n=1, m=1) is a muscarinic antagonist equipotent with Pirenzepine on rabbit vas deferens (M 1-putative) but shows a better selectivity profile.