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 microM, most of the iodomethylates were endowed with promising affinity for the muscarinic receptors.
Dei
Silvia
S
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Gino Capponi 9, 50121 Firenze, Italy.
Bellucci
Cristina
C
Buccioni
Michela
M
Ferraroni
Marta
M
Gualtieri
Fulvio
F
Guandalini
Luca
L
Manetti
Dina
D
Matucci
Rosanna
R
Romanelli
Maria Novella
MN
Scapecchi
Serena
S
Teodori
Elisabetta
E
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004148:Dioxolanes / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D015394:Molecular Structure; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018678:Cholinergic Agents; D004148:Dioxolanes; D011759:Pyrrolidines; D011950:Receptors, Cholinergic; C010962:formal glycol