The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for δ/μ opioid receptor agonists and neurokinin 1 receptor antagonists

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

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6334-6347
Number of pages14
JournalJournal of Medicinal Chemistry
Volume51
Issue number20
DOIs
StatePublished - Oct 23 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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