Biochemical characterisation of newly developed β-etorphine and β-dihydroetorphine derivatives

Dauren Biyashev, Sándor Garadnay, János Marton, Sándor Makleit, Anna Borsodi, Sándor Benyhe

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The highly potent synthetic narcotic compound etorphine is known to cause strong analgesia, catatonia and blockade of conditioned reflexes in laboratory animals and is widely used for the immobilisation of game animals. In this study, a number of new structural analogues of etorphine, including C18-β-structures, 3-O-methylether derivatives and saturated C7-C8 dihydro-compounds, were synthesised and examined in in vitro ligand binding experiments. Opiate receptor-mediated activation of G-proteins by these derivatives was also investigated using the [35S]GTPγS binding assay. The receptor binding affinity constant and G-protein stimulatory potency of the novel β-etorphins were compared with those of the corresponding C18-α-derivatives. In rat brain membrane preparations, all the compounds tested displayed high affinity (Ki's ranging 0.4-22 nM) using [3H]naloxone in competition assays. The α-etorphines had somewhat higher affinity in comparison with the β-structures. Methylether derivatives were consistently weaker than the corresponding phenolic compounds. Dihydroetorphine and β-dihydroetorphine, which have a partially saturated ring structure, showed as good potency in the binding assays as did etorphine and β-etorphine with C7-C8 double bonds. The etorphine derivatives were potent but naloxone-reversible activators of G-proteins in the [35S]GTPγS functional tests. It was also found that the C3 phenolic group is favourable for G-protein activation. On the basis of our experimental results, neither the configuration of C18 nor the saturation of the C7-C8 double bond appears to play a critical role in the biological activity of etorphines.

Original languageEnglish
Pages (from-to)23-27
Number of pages5
JournalEuropean Journal of Pharmacology
Volume442
Issue number1-2
DOIs
Publication statusPublished - May 3 2002

Keywords

  • Brain
  • Etorphine derivative
  • Opioid receptor
  • Radioligand binding
  • Rat
  • [S]GTPγS binding

ASJC Scopus subject areas

  • Pharmacology

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