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

Diastereomer
DOI: 10.1021/jm200937t Publication Date: 2011-09-25T19:07:39Z
ABSTRACT
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.
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