Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects

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• 作者：Morgan Le Naour ; Mary M. Lunzer ; Michael D. Powers ; Alexander E. Kalyuzhny ; Michael A. Benneyworth ; Mark J. Thomas ; Philip S. Portoghese
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6383-6392
• 全文大小：418K
• ISSN：1520-4804

文摘

It is now generally recognized that upon activation by an agonist, 尾-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with 魏 opioid agonists, a series of 尾-naltrexamides 3鈥?b>10 was synthesized in an effort to selectively target putative 魏 opioid heteromers without recruiting 尾-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of 尾-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.