Design, synthesis, and biological evaluation of novel bifunctional C-terminal-modified peptides for δ/μ opioid receptor agonists and neurokinin-1 receptor antagonists

Takashi Yamamoto, Padma Nair, Peg Davis, Shou Wu Ma, Edita Navratilova, Sharif Moye, Suneeta Tumati, Josephine Lai, Todd W. Vanderah, Henry I. Yamamura, Frank Porreca, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

A series of bifunctional peptides that act as agonists for δ and μ opioid receptors with δ selectivity and as antagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application as analgesics in various pain states. The peptides were characterized using radioligand binding assays and functional assays using cell membrane and animal tissue. Optimization was performed on the fifth residue which serves as an address moiety for both receptor recognitions. It had critical effects on both activities at δ/μ opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF 3) 2 (5) and H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5- Bzl(CF3)2 (7) had excellent agonist activity for both δ opioid and μ opioid receptors and excellent antagonist activity for NK1 receptors. These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1 antagonist activities can be accomplished and may provide a new tool for treatment of chronic and several pain states.

Original languageEnglish (US)
Pages (from-to)2779-2786
Number of pages8
JournalJournal of Medicinal Chemistry
Volume50
Issue number12
DOIs
StatePublished - Jun 14 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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