Pharmacological selection of cannabinoid receptor effectors: Signalling, allosteric modulation and bias

Abstract

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 only 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. The development of compounds that selectively activate CB₁ signalling pathways, whether allosterically or via orthosteric agonist bias, will also be addressed.

Keywords: Allosteric modulation; Biased agonism; Cannabinoid receptor; Functional selectivity; G protein coupled receptor; Signal transduction.