Favourable involvement of 伪_2A-adrenoreceptor antagonism in the I₂-imidazoline binding sites-mediated morphine analgesia enhancement

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• 作者：Valerio Mammoli^a ; Alessandro Bonifazi^a ; Fabio Del Bello^a ; Eleonora Diamanti^a ; Mario Giannella^a ; Alan L. Hudson^b ; Laura Mattioli^c ; Marina Perfumi^c ; Alessandro Piergentili^a ; ^{alessandro.piergentili@unicam.it} ; Wilma Quaglia^a ; Federica Titomanlio^c ; Maria Pigini^a
• 关键词：AR ; adrenoreceptor ; PNS ; peripheral nervous system ; CNS ; central nervous system ; IBS ; imidazoline binding sites ; CHO ; Chinese hamster ovary ; (1S)-(+)-10-CSA ; (1S)-(+)-10-camphorsulfonic acid ; m-CPBA ; m-chloroperbenzoic acid ; MPE ; Maximum Possible Effect
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 April, 2012
• 卷：20
• 期：7
• 页码：2259-2265
• 文件大小：385 K

摘要

Aim of the present study was to obtain novel 伪₂-adrenoreceptor (伪₂-AR) antagonists, possibly endowed with subtype-selectivity. Therefore, inspired by the non subtype-selective 伪₂-AR antagonist idazoxan, we designed 1,4-dioxane derivatives bearing an aromatic area in position 5 or 6 and the imidazoline nucleus in position 2. Among the novel molecules 1-6, compound 2, with a trans stereochemical relationship between 5-phenyl and 2-imidazoline groups, was able to antagonize the sole 伪_2A-subtype. Moreover, 2 showed an affinity at I₂-imidazoline binding sites (I₂-IBS) comparable to that at 伪_2A-AR. In in vivo studies 2 strongly increased morphine analgesia. This interesting behaviour appeared to be induced by the favourable involvement of 伪_2A-AR antagonism in the I₂-IBS-mediated morphine analgesia enhancement.