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

• Published in: European journal of medicinal chemistry Vol. 178; pp. 571 - 588
• Main Authors: Dvorácskó, Szabolcs, Keresztes, Attila, Mollica, Adriano, Stefanucci, Azzurra, Macedonio, Giorgia, Pieretti, Stefano, Zádor, Ferenc, Walter, Fruzsina R., Deli, Mária A., Kékesi, Gabriella, Bánki, László, Tuboly, Gábor, Horváth, Gyöngyi, Tömböly, Csaba
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-09-2019
• Subjects: Bivalent ligand; Cannabinoid receptor agonist; Mu opioid receptor agonist; Multi-targeting; Radioligand; Bivalent ligand; Mu opioid receptor agonist; Radioligand; Cannabinoid receptor agonist; PIGFJYFWBSMSFM-WKSKUSBCSA-N; Multi-targeting
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.05.037

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.
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•Mu opioid (oxycodone or Tyr-d-Ala-Gly-Phe-NH2) and cannabinoid (JWH-018) receptor agonists were coupled via short spacers.•JWH-018 was labeled with tritium and [3H]JWH-018 was validated as a novel radioligand for cannabinoid receptors.•In vitro studies revealed that the compounds 11 and 19 could bind both to the mu opioid and to the cannabinoid receptors.•The bivalent compounds 11 and 19 were found to be agonists both for the mu opioid and for the cannabinoid receptors.•At spinal level 11, 19 were equieffective with the parent drugs at 20 μg dose in a chronic osteoarthritis pain model in rats.