5-(2-Pyrrolidinyl)oxazolidinones and 2-(2-pyrrolidinyl)benzodioxanes: synthesis of all the stereoisomers and alpha4beta2 nicotinic affinity.
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.
Pallavicini
Marco
M
Istituto di Chimica Farmaceutica e Tossicologica, Università di Milano Pietro Pratesi, via Mangiagalli 25, I-20133 Milano, Italy. marco.pallavicini@unimi.it
Bolchi
Cristiano
C
Binda
Matteo
M
Cilia
Antonio
A
Clementi
Francesco
F
Ferrara
Rossana
R
Fumagalli
Laura
L
Gotti
Cecilia
C
Moretti
Milena
M
Pedretti
Alessandro
A
Vistoli
Giulio
G
Valoti
Ermanno
E
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
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