2AG

2-Arachidonoylglycerol (2-AG) is an endogenous monoacylglycerol and a principal endocannabinoid in mammals. It is the glycerol ester of arachidonic acid and acts as a signaling lipid that binds to and activates cannabinoid receptors CB1 and CB2, with high efficacy at CB1. In the brain, 2-AG is more abundant than anandamide and participates in retrograde synaptic signaling, modulating neurotransmitter release and influencing synaptic plasticity, learning, and pain processing.

Biosynthesis of 2-AG occurs on demand from diacylglycerol by the enzymes diacylglycerol lipase-α and -β. It is produced in response to neuronal activity and can diffuse from postsynaptic to presynaptic membranes to regulate transmitter release via presynaptic CB1 receptors, functioning as a retrograde messenger.

Metabolism: 2-AG is rapidly hydrolyzed primarily by monoacylglycerol lipase (MAGL) to glycerol and arachidonic acid; alpha/beta-hydrolase domain-containing proteins such as ABHD6 also contribute to its degradation in certain tissues. Due to swift inactivation, 2-AG signaling is transient and tightly controlled.

Distribution and function: 2-AG participates in nociception, appetite regulation, stress responses, and neuroinflammation. Dysregulation of 2-AG signaling has been linked to neurological and psychiatric conditions. Pharmacological approaches that elevate 2-AG, such as MAGL inhibitors, are explored for analgesic and anti-inflammatory effects, though safety concerns related to CB1 activation remain.

Chemistry: The major endogenous form is 2-arachidonoylglycerol; a minor regioisomer, 1-AG, exists in smaller amounts. In CNS tissues, 2-AG is found at low nanomolar concentrations, increasing with neural activity.