Cannabinoid receptor 1 in the context of Tetrahydrocannabivarin

Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It is the principal psychoactive constituent of Cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C₂₁H₃₀O₂) describes multiple isomers, the term THC usually refers to the delta-9-THC isomer with chemical name (−)-trans-Δ-tetrahydrocannabinol. It is a colorless oil.

THC, also known pharmaceutically as dronabinol, is used medically to relieve chemotherapy-induced nausea, HIV/AIDS-related anorexia, and symptoms of multiple sclerosis, including neuropathic pain and spasticity. It acts as a partial agonist at CB₁ and CB₂ cannabinoid receptors.

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system (including the brain) and peripheral nervous system. It is found in animals as simple as hydras, but absent in insects, who are hypothesized to have lost it due to a lack of arachidonic acid. The endocannabinoid system is still not fully understood, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

Two primary cannabinoid receptors have been identified: CB₁, first cloned (or isolated) in 1990; and CB₂, cloned in 1993. CB₁ receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the fatty-acid neurotransmitter anandamide, as well as the most known active component of cannabis, tetrahydrocannabinol (THC). Another endocannabinoid, 2-arachidonoylglycerol (2-AG), also interacts with both CB receptors. It is significantly more abundant in the mammalian brain than anandamide, exceeding it by two to three orders of magnitude.

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands:

• Endocannabinoids;
• Phytocannabinoids (plant-derived such as tetrahydrocannabinol (THC) produced by cannabis);
• Synthetic cannabinoids (such as HU-210).

All endocannabinoids and phytocannabinoids are lipophilic.

JWH-018 (1-pentyl-3-(1-naphthoyl)indole, NA-PIMO or AM-678) is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB₁ and CB₂ cannabinoid receptors, with some selectivity for CB₂. It produces effects in animals similar to those of tetrahydrocannabinol (THC), a cannabinoid naturally present in cannabis, leading to its use as synthetic cannabinoid products that, in some countries, are sold legally as "incense blends".

As a full agonist at both the CB₁ and CB₂ cannabinoid receptors, this chemical compound is classified as an analgesic medication. The analgesic effects of cannabinoid ligands, mediated by CB₁ receptors are well established in treatment of neuropathic pain, as well as cancer pain and arthritis.

The cannabinoid receptor 2 (CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids (plant cannabinoids). The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).

CB2 was cloned in 1993 by a research group from Cambridge looking for a second cannabinoid receptor that could explain the pharmacological properties of tetrahydrocannabinol. The receptor was identified among cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor 1 (CB1) receptor, discovered in 1990. The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system.