Unichiral 2-(2\u2032-Pyrrolidinyl)-1,4-benzodioxanes : the 2R,2\u2032S Diastereomer of the N-Methyl-7-hydroxy Analogue Is a Potent \u3b14\u3b22- and \u3b16\u3b22-Nicotinic Acetylcholine Receptor Partial Agonist

A series of unichiral 7-substituted 2-(1\u2032-methyl-2\u2032- pyrrolidinyl)-1,4-benzodioxanes were synthesized and tested for the affinity for the \u3b14\u3b22 and \u3b17 central nicotinic receptors; the 2R,2\u2032S diastereomer of the 7-OH analogue [(R,S)-7], unique in the series, has a high \u3b14\u3b22 affinity (12nM K i). N-Demethylation and configuration inversion of the stereocenters greatly weaken its \u3b14\u3b22 affinity, confirming that such a rigid molecule can be considered a new template for \u3b14\u3b22 ligands. Docking analysis showed how (R,S)-7 is capable of strongly and specifically interacting with the amino acidic counterpart of the \u3b14\u3b22 receptor binding site. Further pharmacological characterization demonstrated that (R,S)-7 also has a high affinity for the \u3b16\u3b22 receptor, and in vitro functional tests indicated that it is a potent \u3b14\u3b22 and \u3b16\u3b22 partial agonist, with modest affinity and potency for the \u3b13\u3b24 receptor. Comparison with varenicline, a well-known nicotinic partial agonist used as a smoking cessation aid, interestingly reveals similar nicotinoid profiles