4.6 Article

Biased agonism at the cannabinoid receptors - Evidence from synthetic cannabinoid receptor agonists

Journal

CELLULAR SIGNALLING
Volume 78, Issue -, Pages -

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2020.109865

Keywords

Cannabinoid receptors; Functional selectivity; Ligand bias; Synthetic cannabinoid receptor agonists

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SCRAs were originally developed to explore therapeutic benefits of cannabinoid receptor activation, but have been diverted to the recreational drug market, potentially leading to toxicity. Biased agonists can maximize drug effectiveness by reducing adverse effects, but the signaling pathways of cannabinoid receptors are still unclear.
The type 1 and type 2 cannabinoid receptors are G protein-coupled receptors implicated in a variety of physiological processes and diseases. Synthetic cannabinoid receptor agonists (SCRAs) were originally developed to explore the therapeutic benefits of cannabinoid receptor activation, although more recently, these compounds have been diverted to the recreational drug market and are increasingly associated with incidences of toxicity. A prominent concept in contemporary pharmacology is functional selectivity or biased agonism, which describes the ability of ligands to elicit differential activation of signalling pathways through stabilisation of distinct receptor conformations. Biased agonists may maximise drug effectiveness by reducing on-target adverse effects if they are mediated by signalling pathways distinct from those that drive the therapeutic effects. For the cannabinoid receptors, it remains unclear as to which signalling pathways mediate desirable and adverse effects. However, given their structural diversity and potential to induce a plethora of signalling effects, SCRAs provide the most promising prospect for detecting and studying bias at the cannabinoid receptors. This review summarises the emerging evidence of SCRA bias at the cannabinoid receptors.

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