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

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