Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as 伪4尾2-Nicotinic Acetylcholine Recep

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• 作者：Cristiano Bolchi ; Ermanno Valoti ; Cecilia Gotti ; Francesca Fasoli ; Paola Ruggeri ; Laura Fumagalli ; Matteo Binda ; Vanessa Mucchietto ; Miriam Sciaccaluga ; Roberta Budriesi ; Sergio Fucile ; Marco Pallavicini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 27, 2015
• 年：2015
• 卷：58
• 期：16
• 页码：6665-6677
• 全文大小：518K
• ISSN：1520-4804

文摘

Some unichiral analogues of 2R,2鈥?i>S-2-(1鈥?methyl-2鈥?pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective 伪4尾2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high 伪4尾2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High 伪4尾2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known 伪4尾2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the 伪4尾2 and 伪3尾4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of N-methylprolinol are 伪4尾2 full agonists, but only the latter is highly 伪4尾2/伪3尾4 selective, while potent and selective partial 伪4尾2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues.