Unichiral 2-(2鈥?Pyrrolidinyl)-1,4-benzodioxanes: the 2R,2鈥?i>S Diastereomer of the N-Methyl-7-hydroxy Analogue Is a Potent 伪4尾2- and 伪6尾2-Nicotinic Acetylcholine Receptor Partial Ago

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• 作者：Cristiano Bolchi ; Cecilia Gotti ; Matteo Binda ; Laura Fumagalli ; Luca Pucci ; Francesco Pistillo ; Giulio Vistoli ; Ermanno Valoti ; Marco Pallavicini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7588-7601
• 全文大小：1115K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

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