Synthesis and pharmacological characterization of a novel, highly potent, peptidomimetic δ-opioid radioantagonist, [3H]Tyr-Tic-(2S, 3R)-β-MePhe-Phe-OH

Erika Birkas, Istvan Kertesz, Geza Toth, Lidia Bakota, K. Gulya, M. Szücs

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

[3H]Tyr-Tic-(2S, 3R)-β-MePhe-Phe-OH (where Tic: 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) with a specific radioactivity of 53.7 Ci/mmol was synthesized and characterized in receptor binding assays at 25 °C in rat brain membranes. The specific binding was saturable and displayed high affinity, with a KD of 0.16 ± 0.005 nM and Bmax of 85.9 ± 6.3 fmol/mg protein. NaCl increased its affinity by about 4-fold in membranes of rat brain and Chinese Hamster Ovary Cells stably transfected with the human δ-opioid receptors (hDOR-CHO) showing that the new ligand is an antagonist. The prototypic δ-opioid ligands were much more potent than μ- or κ-specific ligands in competition assays. The autoradiographic distribution of the binding sites of the new ligand agreed with the known locations of the δ-opioid receptors in rat brain. The unlabeled new ligand was about 7-fold more potent than the parent peptide in competing for the binding sites of [3H]Tyr-Tic-(2S, 3R)-β-MePhe-Phe-OH in rat brain membranes. Likewise, the threo-β-methyl analog was 3.8-fold more potent than the parent compound in antagonizing the effect of DPDPE in the [35S]GTPγS functional assay in hDOR-CHO membranes. The new, highly potent, conformationally constrained antagonist may be a valuable pharmacological tool in understanding the structural and topographical requirements of peptide ligand binding to the δ-opioid receptors.

Original languageEnglish
Pages (from-to)57-67
Number of pages11
JournalNeuropeptides
Volume42
Issue number1
DOIs
Publication statusPublished - Feb 2008

Fingerprint

Peptidomimetics
Opioid Analgesics
Pharmacology
Ligands
Rats
Brain
Opioid Receptors
Membranes
Assays
Binding Sites
D-Penicillamine (2,5)-Enkephalin
Tics
Peptides
Radioactivity
Cricetulus
2-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
Ovary
Cells

Keywords

  • δ-opioid
  • Antagonist
  • Autoradiography
  • Peptidomimetic
  • Receptor binding
  • TIPP analog

ASJC Scopus subject areas

  • Endocrinology
  • Clinical Neurology
  • Endocrinology, Diabetes and Metabolism
  • Cellular and Molecular Neuroscience
  • Neuroscience(all)
  • Biochemistry

Cite this

Synthesis and pharmacological characterization of a novel, highly potent, peptidomimetic δ-opioid radioantagonist, [3H]Tyr-Tic-(2S, 3R)-β-MePhe-Phe-OH. / Birkas, Erika; Kertesz, Istvan; Toth, Geza; Bakota, Lidia; Gulya, K.; Szücs, M.

In: Neuropeptides, Vol. 42, No. 1, 02.2008, p. 57-67.

Research output: Contribution to journalArticle

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