Opioid receptor binding characteristics and structure-activity studies of novel tetrapeptides in the TIPP (Tyr-Tic-Phe-Phe) series

Eniko Ioja, Géza Tóth, S. Benyhe, Dirk Tourwe, A. Péter, C. Tömböly, A. Borsodi

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The development of the prototype synthetic δ-opioid receptor antagonist peptides TIPP [(H-Tyr-Tic-Phe-Phe-OH); Tic: tetrahydroisoquinoline-3- carboxylic acid] and TIPPψ (H-Tyr-ψTic-Phe-Phe-OH) by Schiller and co-workers was followed by extensive structure-activity relationship studies, leading to the emergence of numerous analogs that are of pharmacological interest. Eight novel diastereomeric compounds in this peptide family were designed, prepared, and tested biologically to gain structure-activity relationship information. The new multisubstituted tetrapeptide analogs contain both a 2′,6′-dimethyltyrosine residue at the N-terminus and β-methyl-cyclohexylalanine at the third position as replacements for the original first tyrosine and the third phenylalanine, respectively. These derivatives wear either free acidic (-COOH) or amidated (-CONH2) C-terminal. The potency and δ- versus μ-opioid receptor selectivity were evaluated by in vitro radioreceptor-binding assays, while the intrinsic G-protein-activating efficacy of these analogs was tested in [ 35S]GTPγS-binding assays using rat brain membranes or Chinese hamster ovary cells stably expressing μ- or δ-opioid receptors. The analogs showed δ-antagonist selectivity with differences regarding their isomeric forms, and these analogs containing a C-terminal carboxamide group displayed a mixed μ-agonist/δ-antagonist profile, thus they are expected to be safer analgesics with a low propensity to produce tolerance and physical dependence. These results constitute further examples of the influence of β-methyl substitution and C-terminal amidation on potency, selectivity, and signal transduction properties of TIPP-related peptides as well as they represent valuable pharmacological tools for opioid research.

Original languageEnglish
Pages (from-to)317-328
Number of pages12
JournalNeuroSignals
Volume14
Issue number6
DOIs
Publication statusPublished - Jun 2006

Fingerprint

phenylalanylphenylalanine
Opioid Receptors
Structure-Activity Relationship
Peptides
Artificial Receptors
Pharmacology
Tics
Radioligand Assay
Narcotic Antagonists
Cricetulus
Phenylalanine
GTP-Binding Proteins
Opioid Analgesics
Tyrosine
Analgesics
Ovary
Signal Transduction
Membranes
Brain
Research

Keywords

  • [ S]GTPγS binding
  • Chinese hamster ovary (CHO) cell lines
  • Delta antagonist peptides
  • Opioid receptors
  • Radioligand binding
  • Rat brain, opioid receptors

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Opioid receptor binding characteristics and structure-activity studies of novel tetrapeptides in the TIPP (Tyr-Tic-Phe-Phe) series. / Ioja, Eniko; Tóth, Géza; Benyhe, S.; Tourwe, Dirk; Péter, A.; Tömböly, C.; Borsodi, A.

In: NeuroSignals, Vol. 14, No. 6, 06.2006, p. 317-328.

Research output: Contribution to journalArticle

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