Might the observed 伪_2A-adrenoreceptor agonism or antagonism of allyphenyline analogues be ascribed to different molecular conformations?

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• 作者：Eleonora Diamanti^a ; Fabio Del Bello^a ; Giuseppe Carbonara^b ; Antonio Carrieri^b ; Giuseppe Fracchiolla^b ; Mario Giannella^a ; Valerio Mammoli^a ; Alessandro Piergentili^a ; Katariina Pohjanoksa^c ; Wilma Quaglia^a ; Mika Scheinin^c ; Maria Pigini^a ; ^{maria.pigini@unicam.it}
• 关键词：AR ; adrenoreceptor ; CHO ; Chinese hamster ovary ; CNS ; central nervous system ; MD ; molecular dynamic ; MR ; molar refractivity ; DME ; 1 ; 2-dimethoxyethane ; NOESY ; Nuclear Overhauser Effect Spectroscopy
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 March, 2012
• 卷：20
• 期：6
• 页码：2082-2090
• 文件大小：1060 K

摘要

We recently reported that the 伪₂-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its 伪_2C-AR agonism), was devoid of sedative side effects (due to its 伪_2A-AR antagonism), prevented and reversed morphine tolerance and dependence. To highlight the molecular characteristics compatible with this behaviour and to obtain novel agents potentially useful in chronic pain and opioid addiction management, the allyl group of 9 was replaced by substituents of moderate steric bulk (MR) and positive or negative lipophilic (蟺) and electronic (蟽) contributions in all the possible combinations. Effective novel 伪_2C-agonists/伪_2A-antagonists (2, 3, 10, 12, and 17) were obtained. This study also demonstrated that contradictory combinations of the physicochemical parameters were similarly able to induce the 伪_2A-activation. Since we had previously observed that the absolute configuration affected only the potency, but not the functional profile of the ligands, we hypothesized that the 伪_2A-activation was governed by a ligand preferred conformation. From a structural overlay investigation it emerged that an extended conformation appeared to be associated with dual 伪_2C-agonism/伪_2A-antagonism, whereas a folded conformation associated with 伪_2C-/伪_2A-agonism.