Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities

Padma Nair, Takashi Yamamoto, Scott Cowell, Vinod Kulkarni, Sharif Moye, Edita Navratilova, Peg Davis, Shou Wu Ma, Todd W Vanderah, Josephine Lai, Frank Porreca, Victor J Hruby

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Several bifunctional peptides were synthesized and characterized based on the pentapeptide-derived ligand NP30 (1: Tyr-DAla-Gly-Phe-Gly-Trp-O-[3′,5′-Bzl(CF<inf>3</inf>)<inf>2</inf>]). Modification and truncation of amino acid residues were performed, and the tripeptide-derived ligand NP66 (11: Dmt-DAla-Trp-NH-[3′,5′-(CF<inf>3</inf>)<inf>2</inf>-Bzl]) was obtained based on the overlapping pharmacophore concept. The Trp<sup>3</sup> residue of ligand 11 works as a message residue for both opioid and NK1 activities. The significance lies in the observation that the approach of appropriate truncation of peptide sequence could lead to a tripeptide-derived chimeric ligand with effective binding and functional activities for both mu and delta opioid and NK1 receptors with agonist activities at mu and delta opioid and antagonist activity at NK1 receptors, respectively.

Original languageEnglish (US)
Pages (from-to)3716-3720
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number17
DOIs
StatePublished - Apr 21 2015

Fingerprint

Neurokinin-1 Receptor Antagonists
Neurokinin-1 Receptors
delta Opioid Receptor
mu Opioid Receptor
Ligands
Opioid Analgesics
Peptides
Narcotic Antagonists
Amino Acids

Keywords

  • Multifunctional ligands
  • Neutokinin-1 receptor antagonists
  • Opioid receptor agonists
  • Truncation of peptide sequence

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities. / Nair, Padma; Yamamoto, Takashi; Cowell, Scott; Kulkarni, Vinod; Moye, Sharif; Navratilova, Edita; Davis, Peg; Ma, Shou Wu; Vanderah, Todd W; Lai, Josephine; Porreca, Frank; Hruby, Victor J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 17, 21.04.2015, p. 3716-3720.

Research output: Contribution to journalArticle

Nair, Padma ; Yamamoto, Takashi ; Cowell, Scott ; Kulkarni, Vinod ; Moye, Sharif ; Navratilova, Edita ; Davis, Peg ; Ma, Shou Wu ; Vanderah, Todd W ; Lai, Josephine ; Porreca, Frank ; Hruby, Victor J. / Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities. In: Bioorganic and Medicinal Chemistry Letters. 2015 ; Vol. 25, No. 17. pp. 3716-3720.
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AU - Nair, Padma

AU - Yamamoto, Takashi

AU - Cowell, Scott

AU - Kulkarni, Vinod

AU - Moye, Sharif

AU - Navratilova, Edita

AU - Davis, Peg

AU - Ma, Shou Wu

AU - Vanderah, Todd W

AU - Lai, Josephine

AU - Porreca, Frank

AU - Hruby, Victor J

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N2 - Several bifunctional peptides were synthesized and characterized based on the pentapeptide-derived ligand NP30 (1: Tyr-DAla-Gly-Phe-Gly-Trp-O-[3′,5′-Bzl(CF3)2]). Modification and truncation of amino acid residues were performed, and the tripeptide-derived ligand NP66 (11: Dmt-DAla-Trp-NH-[3′,5′-(CF3)2-Bzl]) was obtained based on the overlapping pharmacophore concept. The Trp3 residue of ligand 11 works as a message residue for both opioid and NK1 activities. The significance lies in the observation that the approach of appropriate truncation of peptide sequence could lead to a tripeptide-derived chimeric ligand with effective binding and functional activities for both mu and delta opioid and NK1 receptors with agonist activities at mu and delta opioid and antagonist activity at NK1 receptors, respectively.

AB - Several bifunctional peptides were synthesized and characterized based on the pentapeptide-derived ligand NP30 (1: Tyr-DAla-Gly-Phe-Gly-Trp-O-[3′,5′-Bzl(CF3)2]). Modification and truncation of amino acid residues were performed, and the tripeptide-derived ligand NP66 (11: Dmt-DAla-Trp-NH-[3′,5′-(CF3)2-Bzl]) was obtained based on the overlapping pharmacophore concept. The Trp3 residue of ligand 11 works as a message residue for both opioid and NK1 activities. The significance lies in the observation that the approach of appropriate truncation of peptide sequence could lead to a tripeptide-derived chimeric ligand with effective binding and functional activities for both mu and delta opioid and NK1 receptors with agonist activities at mu and delta opioid and antagonist activity at NK1 receptors, respectively.

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KW - Truncation of peptide sequence

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