Herkinorin Analogues with Differential β-Arrestin-2 Interactions

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• 作者：Kevin Tidgewell ; Chad E. Groer ; Wayne W. Harding ; Anthony Lozama ; Matthew Schmidt ; Alfred Marquam ; Jessica Hiemstra ; John S. Partilla ; Christina M. Dersch ; Richard B. Rothman ; Laura M. Bohn ; Thomas E.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 24, 2008
• 年：2008
• 卷：51
• 期：8
• 页码：2421 - 2431
• 全文大小：657K
• 年卷期：v.51,no.8(April 24, 2008)
• ISSN：1520-4804

文摘

Salvinorin A is a psychoactive natural product that has been found to be a potent and selective κ opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent κ opioid receptor signaling yet leads to less receptor downregulation than observed with other κ agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin (1c), with high affinity at the μOR. We recently reported that 1c does not promote the recruitment of β-arrestin-2 to the μOR or receptor internalization. Here we describe three new derivatives of 1c (3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of β-arrestin-2 to the μOR and receptor internalization. When the important role μ opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, μ opioids derived from salvinorin A may offer a unique template for the development of functionally selective μ opioid receptor–ligands with the ability to produce analgesia while limiting adverse side effects.