A comprehensive study on the putative δ-opioid receptor (sub)types using the highly selective δ-antagonist, Tyr-Tic-(2S,3R)-β-MePhe-Phe- OH

Erika Birkas, Lidia Bakota, Karoly Gulya, Ting Wen, John Pintar, Geza Tóth, Maria Szucs

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The goal of our work was a throughout characterization of the pharmacology of the TIPP-analog, Tyr-Tic-(2S,3R)-β-MePhe-Phe-OH and see if putative δ-opioid receptor subtypes can be distinguished. Analgesic latencies were assessed in mouse tail-flick assays after intrathecal administration. In vitro receptor autoradiography, binding and ligand-stimulated [ 35S] GTPγS functional assays were performed in the presence of putative δ 1-(DPDPE: agonist, BNTX: antagonist), δ 2- (agonist: deltorphin II, Ile 5,6-deltorphin II, antagonist: naltriben) and μ-(DAMGO: agonist) opioid ligands. The examined antagonist inhibited the effect of DPDPE by 60%, but did not antagonize δ 2- and μ-agonist induced analgesia. The radiolabeled form identified binding sites with K D = 0.18 nM and receptor densities of 102.7 fmol/mg protein in mouse brain membranes. The binding site distribution of the [ 3H]Tyr-Tic-(2S,3R)-β-MePhe-Phe-OH agreed well with that of [ 3H]Ile 5,6-deltorphin II as revealed by receptor autoradiography. Tyr-Tic-(2S,3R)-β-MePhe-Phe-OH displayed 2.49 ± 0.06 and 0.30 ± 0.01 nM potency against DPDPE and deltorphin II in the [ 35S]GTPγS functional assay, respectively. The rank order of potency of putative δ 1- and δ 2-antagonists against DPDPE and deltorphin was similar in brain and CHO cells expressing human δ-opioid receptors. Deletion of the DOR-1 gene resulted in no residual binding of the radioligand and no significant DPDPE effect on G-protein activation. Tyr-Tic-(2S,3R)-β-MePhe-Phe-OH is a highly potent and δ-opioid specific antagonist both in vivo and in vitro. However, the putative δ 1- and δ 2-opioid receptors could not be unequivocally distinguished in vitro.

Original languageEnglish
Pages (from-to)192-201
Number of pages10
JournalNeurochemistry international
Issue number2
Publication statusPublished - Aug 1 2011



  • Mouse brain
  • TIPP analog
  • δ-Opioid antagonist
  • δ-Opioid knock-out
  • δ-Opioid receptor subtypes

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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