Potent μ-Opioid Receptor Agonists from Cyclic Peptides Tyr-c[d-Lys-Xxx-Tyr-Gly]: Synthesis, Biological, and Structural Evaluation

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• 作者：Yangmei Li ; Margret Cazares ; Jinhua Wu ; Richard A. Houghten ; Laurence Toll ; Colette Dooley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：1239-1245
• 全文大小：321K
• ISSN：1520-4804

文摘

To optimize the structure of a μ-opioid receptor ligand, analogs H-Tyr-c[d-Lys-Xxx-Tyr-Gly] were synthesized and their biological activity was tested. The analog containing a Phe³ was identified as not only exhibiting binding affinity 14-fold higher than the original hit but also producing agonist activity 3-fold more potent than morphine. NMR study suggested that a trans conformation at d-Lys²-Xxx³ is crucial for these cyclic peptides to maintain high affinity, selectivity, and functional activity toward the μ-opioid receptor.