Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors

Szabolcs Dvorácskó, Attila Keresztes, Adriano Mollica, Azzurra Stefanucci, Giorgia Macedonio, Stefano Pieretti, Ferenc Zádor, Fruzsina R. Walter, Mária A. Deli, G. Kékesi, László Bánki, Gábor Tuboly, G. Horváth, C. Tömböly

Research output: Contribution to journalArticle

Abstract

In order to obtain novel pharmacological tools and to investigate a multitargeting analgesic strategy, the CB1 and CB2 cannabinoid receptor agonist JWH-018 was conjugated with the opiate analgesic oxycodone or with an enkephalin related tetrapeptide. The opioid and cannabinoid pharmacophores were coupled via spacers of different length and chemical structure. In vitro radioligand binding experiments confirmed that the resulting bivalent compounds bound both to the opioid and to the cannabinoid receptors with moderate to high affinity. The highest affinity bivalent derivatives 11 and 19 exhibited agonist properties in [35S]GTPγS binding assays. These compounds activated MOR and CB (11 mainly CB2, whereas 19 mainly CB1) receptor-mediated signaling, as it was revealed by experiments using receptor specific antagonists. In rats both 11 and 19 exhibited antiallodynic effect similar to the parent drugs in 20 μg dose at spinal level. These results support the strategy of multitargeting G-protein coupled receptors to develop lead compounds with antinociceptive properties.

Original languageEnglish
Pages (from-to)571-588
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume178
DOIs
Publication statusPublished - Sep 15 2019

Fingerprint

Cannabinoid Receptors
mu Opioid Receptor
Opioid Analgesics
Analgesics
Opiate Alkaloids
Oxycodone
Cannabinoid Receptor Agonists
Lead compounds
Cannabinoid Receptor CB1
Cannabinoids
Enkephalins
G-Protein-Coupled Receptors
Rats
Assays
Experiments
Pharmacology
Derivatives
Pharmaceutical Preparations
1-pentyl-3-(1-naphthoyl)indole
In Vitro Techniques

Keywords

  • Bivalent ligand
  • Cannabinoid receptor agonist
  • Mu opioid receptor agonist
  • Multi-targeting
  • PIGFJYFWBSMSFM-WKSKUSBCSA-N
  • Radioligand

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors. / Dvorácskó, Szabolcs; Keresztes, Attila; Mollica, Adriano; Stefanucci, Azzurra; Macedonio, Giorgia; Pieretti, Stefano; Zádor, Ferenc; Walter, Fruzsina R.; Deli, Mária A.; Kékesi, G.; Bánki, László; Tuboly, Gábor; Horváth, G.; Tömböly, C.

In: European Journal of Medicinal Chemistry, Vol. 178, 15.09.2019, p. 571-588.

Research output: Contribution to journalArticle

Dvorácskó, S, Keresztes, A, Mollica, A, Stefanucci, A, Macedonio, G, Pieretti, S, Zádor, F, Walter, FR, Deli, MA, Kékesi, G, Bánki, L, Tuboly, G, Horváth, G & Tömböly, C 2019, 'Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors', European Journal of Medicinal Chemistry, vol. 178, pp. 571-588. https://doi.org/10.1016/j.ejmech.2019.05.037
Dvorácskó S, Keresztes A, Mollica A, Stefanucci A, Macedonio G, Pieretti S et al. Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors. European Journal of Medicinal Chemistry. 2019 Sep 15;178:571-588. https://doi.org/10.1016/j.ejmech.2019.05.037
Dvorácskó, Szabolcs ; Keresztes, Attila ; Mollica, Adriano ; Stefanucci, Azzurra ; Macedonio, Giorgia ; Pieretti, Stefano ; Zádor, Ferenc ; Walter, Fruzsina R. ; Deli, Mária A. ; Kékesi, G. ; Bánki, László ; Tuboly, Gábor ; Horváth, G. ; Tömböly, C. / Preparation of bivalent agonists for targeting the mu opioid and cannabinoid receptors. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 178. pp. 571-588.
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