The Importance of Micelle-Bound States for the Bioactivities of Bifunctional Peptide Derivatives for δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists

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• 作者：Takashi Yamamoto ; Padma Nair ; Neil E. Jacobsen ; Peg Davis ; Shou-wu Ma ; Edita Navratilova ; Sharif Moye ; Josephine Lai ; Henry I. Yamamura ; Todd W. Vanderah ; Frank Porreca ; Victor J. Hruby
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 23, 2008
• 年：2008
• 卷：51
• 期：20
• 页码：6334-6347
• 全文大小：309K
• 年卷期：v.51,no.20(October 23, 2008)
• ISSN：1520-4804

文摘

To provide new insight into the determining factors of membrane-bound peptide conformation that might play an important role in peptide−receptor docking and further biological behaviors, the dodecylphosphocholine (DPC) micelle-bound conformations of bifunctional peptide derivatives of δ-preferring opioid agonists and NK1 antagonists (1: Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF₃)₂; 2: Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3,5-Bzl(CF₃)₂; 3: Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bzl) were determined based on 2D NMR studies. Although the differences in the primary sequence were limited to the C-terminus, the obtained NMR conformations were unexpectedly different for each compound. Moreover, their biological activities showed different trends in direct relation to the compound-specific conformations in DPC micelles. The important result is that not only were the NK1 antagonist activities different (the pharmacophore located at the C-terminus)but the opioid agonist activities (this pharmacophore was at the structurally preserved N-terminus) also were shifted, suggesting that a general conformational change in the bioactive state was induced due to relatively small and limited structural modifications.