Unichiral 2-(2′-Pyrrolidinyl)-1,4-benzodioxanes: the 2R,2′S Diastereomer of the N-Methyl-7-hydroxy Analogue Is a Potent α4β2- and α6β2-Nicotinic Acetylcholine Receptor Partial Agonist

• DOI: 10.1021/jm200937t
• Publication Date: 2011-09-25T19:07:39Z
• Authors: Cristiano Bolchi; Cecilia Gotti; Matteo Binda; Laura Fumagalli; Luca Pucci; Francesco Pistillo; Giulio Vistoli; Ermanno Valoti; Marco Pallavicini
• Keywords: Diastereomer

A series of unichiral 7-substituted 2-(1'-methyl-2'-pyrrolidinyl)-1,4-benzodioxanes were synthesized and tested for the affinity α4β2 α7 central nicotinic receptors; 2R,2'S diastereomer 7-OH analogue [(R,S)-7], unique in series, has a high (12nM K(i)). N-Demethylation configuration inversion stereocenters greatly weaken its affinity, confirming that such rigid molecule can be considered new template ligands. Docking analysis showed how (R,S)-7 is capable strongly specifically interacting with amino acidic counterpart receptor binding site. Further pharmacological characterization demonstrated also α6β2 receptor, vitro functional tests indicated it potent partial agonist, modest potency α3β4 receptor. Comparison varenicline, well-known agonist used as smoking cessation aid, interestingly reveals similar nicotinoid profiles.