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, Jo Palandri, Chris P Bailey, Ingemar Starke, Bengt von Mentzer, David Kendall, Eamonn Kelly

Research output: Contribution to journalArticle

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 internalisation 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. SIGNIFICANCE STATEMENT: PN6047 is a selective, G protein-biased δ opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment and PN6047 does not display pro-convulsant activity or other opioid-mediated adverse effects. Our data suggest that δ opioid ligands with limited arrestin signalling will be beneficial in the treatment of chronic pain.

Original languageEnglish
JournalJournal of Pharmacology and Experimental Therapeutics
Early online date8 Oct 2019
DOIs
Publication statusE-pub ahead of print - 8 Oct 2019

Cite this

A novel G protein-biased agonist at the δ opioid receptor with analgesic efficacy in models of chronic pain. / Conibear, Alexandra E; Asghar, Junaid; Hill, Rob; Henderson, Graeme; Borbely, Eva; Tekus, Valeria; Helyes, Zsuzsanna; Palandri, Jo; Bailey, Chris P; Starke, Ingemar; von Mentzer, Bengt; Kendall, David; Kelly, Eamonn.

In: Journal of Pharmacology and Experimental Therapeutics, 08.10.2019.

Research output: Contribution to journalArticle

Conibear, AE, Asghar, J, Hill, R, Henderson, G, Borbely, E, Tekus, V, Helyes, Z, Palandri, J, Bailey, CP, Starke, I, von Mentzer, B, Kendall, D & Kelly, E 2019, 'A novel G protein-biased agonist at the δ opioid receptor with analgesic efficacy in models of chronic pain', Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1124/jpet.119.258640
Conibear, Alexandra E ; Asghar, Junaid ; Hill, Rob ; Henderson, Graeme ; Borbely, Eva ; Tekus, Valeria ; Helyes, Zsuzsanna ; Palandri, Jo ; Bailey, Chris P ; Starke, Ingemar ; von Mentzer, Bengt ; Kendall, David ; Kelly, Eamonn. / A novel G protein-biased agonist at the δ opioid receptor with analgesic efficacy in models of chronic pain. In: Journal of Pharmacology and Experimental Therapeutics. 2019.
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T1 - A novel G protein-biased agonist at the δ opioid receptor with analgesic efficacy in models of chronic pain

AU - Conibear, Alexandra E

AU - Asghar, Junaid

AU - Hill, Rob

AU - Henderson, Graeme

AU - Borbely, Eva

AU - Tekus, Valeria

AU - Helyes, Zsuzsanna

AU - Palandri, Jo

AU - Bailey, Chris P

AU - Starke, Ingemar

AU - von Mentzer, Bengt

AU - Kendall, David

AU - Kelly, Eamonn

N1 - The American Society for Pharmacology and Experimental Therapeutics.

PY - 2019/10/8

Y1 - 2019/10/8

N2 - 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 internalisation 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. SIGNIFICANCE STATEMENT: PN6047 is a selective, G protein-biased δ opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment and PN6047 does not display pro-convulsant activity or other opioid-mediated adverse effects. Our data suggest that δ opioid ligands with limited arrestin signalling will be beneficial in the treatment of chronic pain.

AB - 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 internalisation 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. SIGNIFICANCE STATEMENT: PN6047 is a selective, G protein-biased δ opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment and PN6047 does not display pro-convulsant activity or other opioid-mediated adverse effects. Our data suggest that δ opioid ligands with limited arrestin signalling will be beneficial in the treatment of chronic pain.

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DO - 10.1124/jpet.119.258640

M3 - Article

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

ER -