Discovery of Potent and Selective Agonists of δ Opioid Receptor by Revisiting the “Message-Address” Concept

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• 作者：Qing Shen ; Yuanyuan Qian ; Xiaoqin Huang ; Xuejun Xu ; Wei Li ; Jinggen Liu ; Wei Fu
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：391-396
• 全文大小：407K
• 年卷期：0
• ISSN：1948-5875

文摘

The classic “message-address” concept was proposed to address the binding of endogenous peptides to the opioid receptors and was later successfully applied in the discovery of the first nonpeptide δ opioid receptor (DOR) antagonist naltrindole. By revisiting this concept, and based on the structure of tramadol, we designed a series of novel compounds that act as highly potent and selective agonists of DOR among which (−)-6j showed the highest affinity (K_i = 2.7 nM), best agonistic activity (EC₅₀ = 2.6 nM), and DOR selectivity (more than 1000-fold over the other two subtype opioid receptors). Molecular docking studies suggest that the “message” part of (−)-6j interacts with residue Asp128^3.32 and a neighboring water molecule, and the “address” part of (−)-6j packs with hydrophobic residues Leu300^7.35, Val281^6.55, and Trp284^6.58, rendering DOR selectivity. The discovery of novel compound (−)-6j, and the obtained insights into DOR-agonist binding will help us design more potent and selective DOR agonists.