A novel G protein-biased agonist at the δ opioid receptor with analgesic efficacy in models of chronic pain

Alexandra E Conibear, Junaid Asghar, Rob Hill, Graeme Henderson, Eva Borbely, Valeria Tekus, Zsuzsanna Helyes, Josephine Palandri, Chris Bailey, Ingemar Starke, Bengt von Mentzer, David Kendall, Eamonn Kelly

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Agonists at the δ opioid receptor are known to be potent anti-hyperalgesics in chronic pain models and to be effective in models of anxiety and depression. However, some δ opioid agonists have pro-convulsant properties whilst tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the δ opioid receptor differentially engage signalling and regulatory pathways with significant effects on behavioural outcomes. As such, interest is now growing in the development of biased agonists as a potential means to target specific signalling pathways and potentially improve the therapeutic profile of δ opioid agonists. Here we report on PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide) a novel G protein-biased and selective δ opioid agonist. In cell based assays PN6047 fully engages G protein signalling but is a partial agonist in both the arrestin recruitment and internalization assays. PN6047 is effective in rodent models of chronic pain but shows no detectable analgesic tolerance following prolonged treatment. In addition, PN6047 exhibited antidepressant-like activity in the forced swim test and importantly, the drug had no effect on chemically induced seizures. PN6047 did not exhibit reward-like properties in the conditioned place preference test or induce respiratory depression. Thus, δ opioid ligands with limited arrestin signalling such as PN6047 may be therapeutically beneficial in the treatment of chronic pain states.

Original languageEnglish
Pages (from-to)224-236
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume372
Issue number2
Early online date8 Oct 2019
DOIs
Publication statusPublished - 20 Jan 2020

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