Synthesis, biochemical, pharmacological characterization and in silico profile modelling of highly potent opioid orvinol and thevinol derivatives

Edina Szűcs, János Marton, Zoltán Szabó, Sándor Hosztafi, Gabriella Kékesi, Gábor Tuboly, László Bánki, Gyöngyi Horváth, Pál T. Szabó, Csaba Tömböly, Zsuzsanna Katalin Varga, Sándor Benyhe, Ferenc Ötvös

Research output: Contribution to journalArticle

Abstract

Morphine and its derivatives play inevitably important role in the μ-opioid receptor (MOR) targeted antinociception. A structure-activity relationship study is presented for novel and known orvinol and thevinol derivatives with varying 3-O, 6-O, 17-N and 20-alkyl substitutions starting from agonists, antagonists and partial agonists. In vitro competition binding experiments with [3H]DAMGO showed low subnanomolar affinity to MOR. Generally, 6-O-demethylation increased the affinity toward MOR and decreased the efficacy changing the pharmacological profile in some cases. In vivo tests in osteoarthritis inflammation model showed significant antiallodynic effects of thevinol derivatives while orvinol derivatives did not. The pharmacological character was modelled by computational docking to both active and inactive state models of MOR. Docking energy difference for the two states separates agonists and antagonists well while partial agonists overlapped with them. An interaction pattern of the ligands, involving the interacting receptor atoms, showed more efficient separation of the pharmacological profiles. In rats, thevinol derivatives showed antiallodynic effect in vivo. The orvinol derivatives, except for 6-O-desmethyl-dihydroetorfin (2c), did not show antiallodynic effect.

Original languageEnglish
Article number112145
JournalEuropean Journal of Medicinal Chemistry
Volume191
DOIs
Publication statusPublished - Apr 1 2020

    Fingerprint

Keywords

  • 6,14-Ethenomorphinan derivatives
  • Binding
  • Efficacy
  • G-protein
  • Interaction fingerprint
  • Mu-opioid
  • Osteoarthritis inflammation model

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Szűcs, E., Marton, J., Szabó, Z., Hosztafi, S., Kékesi, G., Tuboly, G., Bánki, L., Horváth, G., Szabó, P. T., Tömböly, C., Varga, Z. K., Benyhe, S., & Ötvös, F. (2020). Synthesis, biochemical, pharmacological characterization and in silico profile modelling of highly potent opioid orvinol and thevinol derivatives. European Journal of Medicinal Chemistry, 191, [112145]. https://doi.org/10.1016/j.ejmech.2020.112145