Discovery of a potent and efficacious peptide derivative for δ/μ opioid agonist/neurokinin 1 antagonist activity with a 2′,6′- Dimethyl- l -tyrosine: In vitro, in vivo, and NMR-based structural studies

Takashi Yamamoto, Padma Nair, Tally M. Largent-Milnes, Neil E. Jacobsen, Peg Davis, Shou Wu Ma, Henry I. Yamamura, Todd W. Vanderah, Frank Porreca, Josephine Lai, Victor J. Hruby

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Multivalent ligands with δ/μ opioid agonist and NK1 antagonist activities have shown promising analgesic potency without detectable sign of toxicities, including motor skill impairment and opioid-induced tolerance. To improve their biological activities and metabolic stability, structural optimization was performed on our peptide-derived lead compounds by introducing 2′,6′-dimethyl-l-tyrosine (Dmt) instead of Tyr at the first position. The compound 7 (Dmt-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3′, 5′-(CF3)2-Bzl]) showed improved multivalent bioactivities compared to those of the lead compounds, had more than 6 h half-life in rat plasma, and had significant antinociceptive efficacy in vivo. The NMR structural analysis suggested that Dmt1 incorporation in compound 7 induces the structured conformation in the opioid pharmacophore (N-terminus) and simultaneously shifts the orientation of the NK1 pharmacophore (C-terminus), consistent with its affinities and activities at both opioid and NK1 receptors. These results indicate that compound 7 is a valuable research tool to seek a novel analgesic drug.

Original languageEnglish (US)
Pages (from-to)2029-2038
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
StatePublished - Apr 14 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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