Pharmacological Selection of Cannabinoid Receptor Effectors; Signalling, Allosteric Modulation and Bias

The type-1 cannabinoid receptor (CB1) is a promising drug target for a wide range of diseases. However, many existing and novel candidate ligands for CB1 have shown limited therapeutic potential. Indeed, no ligands are currently approved for the clinic except formulations of the phytocannabinoids Δ9-THC and CBD and a small number of analogues. A key limitation of many promising CB1 ligands are their on-target adverse effects, notably including psychoactivity (agonists) and depression/suicidal ideation (inverse agonists). Recent drug development attempts have therefore focussed on altering CB1 signalling profiles in two ways. Firstly, with compounds that enhance or reduce the signalling of endogenous (endo-) cannabinoids, namely allosteric modulators. Secondly, with compounds that probe the capability of selectively targeting specific cellular signalling pathways that may mediate therapeutic effects using biased ligands. This review will summarise the current paradigm of CB1 signalling in terms of the intracellular transduction pathways acted on by the receptor, their endpoints, and the development of compounds to selectively activate these pathways, whether allosterically or via orthosteric bias.Peer Reviewe