Cannabinoid receptor type 1 and Cannabinoid receptor type 2 (CB1, CB2)

CB1 and CB2 receptors are members of the G protein-coupled receptor (GPCR) superfamily, each with seven transmembrane domains. CB1 is highly expressed in the central nervous system (brain, spinal cord), where it modulates neurotransmitter release, pain, mood, appetite, cognition, and metabolism. CB1 activation causes most psychotropic effects of cannabinoids like THC. CB2 is predominantly found in immune cells and peripheral tissues, regulating inflammation, immune cell migration, and cytokine release; it is also present at lower levels in the CNS. Both receptors engage endogenous cannabinoids (anandamide, 2-AG), plant cannabinoids, and synthetic agents, resulting in diverse biological effects. While CB1 drugs face challenges from psychiatric adverse effects, CB2-selective drugs offer promise for treating inflammation, pain, neurodegeneration, and psychiatric diseases with reduced unwanted CNS effects. Drug development is complicated by high receptor homology, which makes selective ligand design difficult, but recent discoveries of allosteric sites offer new hope for creating more selective modulators.

Other names

Cannabinoid receptor 1 (CB1R)Cannabinoid receptor 2 (CB2R)Central cannabinoid receptor (CB1)Peripheral cannabinoid receptor (CB2)CNR1 (gene for CB1)CNR2 (gene for CB2)

Agonists: Activate the receptor, leading to downstream signaling via Gαi/o proteins (inhibiting adenylyl cyclase, modulating MAPK pathways, affecting ion channels). Antagonists/inverse agonists: Block or reverse normal signaling, used in obesity and addiction (but with psychiatric side effects for CB1). Allosteric modulators: Bind non-orthosteric sites to modify receptor function with potential selectivity. Biased signaling: Selective activation of specific pathways (e.g., G protein vs. β-arrestin).