title: 5-(2-Pyrrolidinyl)oxazolidinones and 2-(2-pyrrolidinyl)benzodioxanes: synthesis of all the stereoisomers and alpha4beta2 nicotinic affinity.
abstract: The four stereoisomers of 2-oxazolidinone 5-substituted with 1-methyl-2-pyrrolidinyl (1), of 1,4-benzodioxane 2-substituted with the same residue (2) and of the nor-methyl analogue of this latter (2a) were synthesized as candidate nicotinoids. Of the 12 compounds, two N-methylated pyrrolidinyl-benzodioxane stereoisomers, namely those with the same relative configuration at the pyrrolidine stereocentre as (S)-nicotine, bind at alpha4beta2 nicotinic acetylcholine receptor with submicromolar affinity. Consistently with the biological data, docking analysis enlightens significant differences in binding site interactions not only between 1 and 2, but also between 2 and 2a and between the stereoisomers of 2 accounting for the critical role played, in the case of the pyrrolidinyl-benzodioxanes, by the chirality of both the stereolabile and stereostable stereogenic atoms, namely the protonated tertiary nitrogen and the two asymmetric carbons.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università di Milano Pietro Pratesi, via Mangiagalli 25, I-20133 Milano, Italy. marco.pallavicini@unimi.it
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Matteo
authors.initials: M
authors.lastname: Binda
authors.forename: Antonio
authors.initials: A
authors.lastname: Cilia
authors.forename: Francesco
authors.initials: F
authors.lastname: Clementi
authors.forename: Rossana
authors.initials: R
authors.lastname: Ferrara
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Milena
authors.initials: M
authors.lastname: Moretti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pedretti
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002244:Carbon / Q000737:chemistry; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis*; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C539895:2-(2-pyrrolidinyl)benzodioxane; D004146:Dioxanes; D008024:Ligands; D023303:Oxazolidinones; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D002244:Carbon; C025223:1,4-dioxane; D000109:Acetylcholine