Synthesis and Cholinergic Affinity of Diastereomeric and Enantiomeric Isomers of 1-Methyl-2-(2-methyl-1,3-dioxolan-4-yl)-pyrrolidine, 1-Methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine and of Their Iodomethylates

Four out of the eight possible stereoisomers of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidine, 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine and the corresponding iodomethylates have been synthesised. They were formally derived from hybridisation of potent though unselective agonists studied before, such as 1,3-dioxolane 1 and 1,3-oxathiolane 2, with the structure of nicotine. It was expected that, by exalting the molecular complexity of the parent compounds, in particular through stereochemical complication in the proximity of the critical cationic head of the molecule, the chance to find agonists able to discriminate among cholinergic receptors subtypes would increase. The relative and absolute configuration of the compounds obtained has been established by means of NMR spectroscopy and X-ray crystallography. In preliminary studies, their binding affinity has been evaluated on rat brain nicotinic and muscarinic receptors. While none of the compounds showed any nicotinic affinity up to the dose of 10 μM, most of the iodomethylates were endowed with promising affinity for the muscarinic receptors.