Assessment of Biased Agonism among Distinct Synthetic Cannabinoid Receptor Agonist Scaffolds

Elise Wouters, Jolien Walraed, Michael Joseph Robertson, Max Meyrath, Martyna Szpakowska, Andy Chevigné, Georgios Skiniotis, Christophe Stove*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)


Cannabinoid receptor 1 (CB1) is a key drug target for a number of diseases, including metabolic syndromes and neuropathic pain. Most of the typical cannabinoid ligands provoke psychotropic side effects that impair their therapeutic utility. As of today, it is not yet clearly known which structural features of cannabinoid ligands determine a preference toward specific signaling pathways. Distinct bioassays are typically used to elucidate signaling preferences. However, these are often based on different cell lines and use different principles and/or read-outs, which makes straightforward assessment of "ligand bias" difficult. Within this context, this study is the first to investigate ligand bias among synthetic cannabinoid receptor agonists (SCRAs) in as closely analogous conditions as possible, by applying a new functional complementation-based assay panel to assess the recruitment of Gαi protein or β-arrestin2 to CB1. In a panel of 21 SCRAs, chosen to cover a broad diversity in chemical structures, distinct, although often subtle, preferences toward specific signaling pathways were observed. Relative to CP55940, here considered as a "balanced" reference agonist, most of the selected SCRAs (e.g., 5F-APINACA, CUMYL-PEGACLONE, among others) displayed preferred signaling through the β-arrestin2 pathway, whereas MMB-CHMICA could serve as a potential "balanced" agonist. Interestingly, EG-018 was the only SCRA showing a significant (10-fold) preference toward G protein over β-arrestin2 recruitment. While it is currently unclear what this exactly means in terms of abuse potential and/or toxicity, the approach proposed here may allow construction of a knowledge base that in the end may allow better insight into the structure-"functional" activity relationship of these compounds. This may aid the development of new therapeutics with less unwanted psychoactive effects.

Original languageEnglish
Pages (from-to)285-295
Number of pages11
JournalACS Pharmacology and Translational Science
Issue number2
Publication statusPublished - 10 Apr 2020


  • G protein
  • G protein-coupled receptor
  • biased signaling
  • cannabinoid receptor
  • synthetic cannabinoid receptor agonist
  • β-arrestin


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