Pharmacology of Cannabinoid Receptor Ligands

TLDR

Mammalian tissues express two cannabinoid receptors, CB1 mainly in neurons and CB2 in immune cells, and the discovery of endogenous ligands has spurred interest in therapeutic applications and the development of selective ligands. This review summarizes current in‑vitro pharmacological knowledge of key CB1 and CB2 receptor ligands. The review details ligand binding characteristics, agonist efficacies measured by cAMP or 35S‑GTPγS assays, structure–activity relationships, and discusses antagonists and inverse agonists that produce opposite tissue effects.

Abstract

Mammalian tissues contain at least two types of cannabinoid receptor, CB<sub>1</sub> and CB<sub>2</sub> , both coupled to G proteins. CB<sub>1</sub> receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB<sub>2</sub> receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this 'endogenous cannabinoid system' has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB<sub>1</sub> or CB<sub>2</sub> receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB<sub>1</sub> and CB<sub>2</sub> receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [<sup>35</sup>S]GTPγS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB<sub>1</sub> or CB<sub>2</sub> receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such 'inverse cannabimimetic effects' are inverse agonists rather than pure antagonists is discussed.