摘要
A series of unichiral 7-substituted 2-(1'-methyl-2'pyrrolidinyl)-1,4-benzodioxanes were synthesized and tested for the affinity for the alpha 4 beta 2 and alpha 7 central nicotinic receptors; the 2R,2'S diastereomer of the 7-OH analogue [(R,S)-7], unique in the series, has a high alpha 4 beta 2 affinity (12nM K(i)). N-Demethylation and configuration inversion of the stereocenters greatly weaken its alpha 4 beta 2 affinity, confirming that such a rigid molecule can be considered a new template for alpha 4 beta 2 ligands. Docking analysis showed how (R,S)-7 is capable of strongly and specifically interacting with the amino acidic counterpart of the alpha 4 beta 2 receptor binding site. Further pharmacological characterization demonstrated that (R,S)-7 also has a high affinity for the alpha 6 beta 2 receptor, and in vitro functional tests indicated that it is a potent alpha 4 beta 2 and alpha 6 beta 2 partial agonist, with modest affinity and potency for the alpha 3 beta 4 receptor. Comparison with varenicline, a well-known nicotinic partial agonist used as a smoking cessation aid, interestingly reveals similar nicotinoid profiles.
- 出版日期2011-11-10