Cannabinoid receptor

class=skin-invert-image|thumb|237px|[[Cannabinoid receptor 1|CB₁ and CB₂ structures]]

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. and in parts of the brain.

The protein sequences of CB₁ and CB₂ receptors are about 44% similar.

Enzymes involved in biosynthesis/inactivation of endocannabinoids and endocannabinoid signaling in general (involving targets other than CB1/2-type receptors) occur throughout the animal kingdom.

Discovery

The existence of cannabinoid receptors in the brain was discovered from in vitro studies in the 1980s, with the receptor designated as the cannabinoid receptor type 1 or CB1. The DNA sequence that encodes a G-protein-coupled cannabinoid receptor in the human brain was identified and cloned in 1990. These discoveries led to determination in 1993 of a second brain cannabinoid receptor named cannabinoid receptor type 2 or CB2. followed by discovery of other fatty acid neurotransmitters that behave as endogenous cannabinoids having a low-to-high range of efficacy for stimulating CB1 receptors in the brain and CB2 receptors in the periphery. They also have a function in keratinocytes. They are also expressed on peripheral nerve terminals. These receptors play a role in antinociception, or the relief of pain. In the brain, they are mainly expressed by microglial cells, where their role remains unclear. While the most likely cellular targets and executors of the CB₂ receptor-mediated effects of endocannabinoids or synthetic agonists are the immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kupffer cells in the liver, astrocytes, etc.), the number of other potential cellular targets is expanding, now including endothelial and smooth muscle cells, fibroblasts of various origins, cardiomyocytes, and certain neuronal elements of the peripheral or central nervous systems (2011).

Signaling

Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.

Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones, however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors —anandamide and 2-arachidonylglycerol (2-AG)— produce most of their effects by binding to both the CB₁ and CB₂ cannabinoid receptors. While the effects mediated by CB₁, mostly in the central nervous system, have been thoroughly investigated, those mediated by CB₂ are not equally well defined.

Prenatal cannabis exposure (PCE) has been shown to perturb the fetal endogenous cannabinoid signaling system. This perturbation has not been shown to directly affect neurodevelopment nor cause lifelong cognitive, behavioral, or functional abnormalities, but it may predispose offspring to abnormalities in cognition and altered emotionality from post-natal factors. Additionally, PCE may alter the wiring of brain circuitry in foetal development and cause significant molecular modifications to neurodevelopmental programs that may lead to neurophysiological disorders and behavioural abnormalities.

Cannabinoid treatments

Synthetic tetrahydrocannabinol (THC) is prescribed under the INN dronabinol or the brand name Marinol, to treat vomiting and for enhancement of appetite, mainly in people with AIDS as well as for refractory nausea and vomiting in people undergoing chemotherapy. Use of synthetic THC is becoming more common as the known benefits become more prominent within the medical industry. THC is also an active ingredient in nabiximols, a specific extract of Cannabis that was approved as a botanical drug in the United Kingdom in 2010 as a mouth spray for people with multiple sclerosis to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.

Ligands

Binding affinity and selectivity of cannabinoid ligands:

{| class="wikitable sortable" style="font-size: smaller; text-align: center; width: auto;"

|-

! style="width: 12em"|

! CB₁ affinity (K_i)

! Efficacy towards CB₁

! CB₂ affinity (K_i)

! Efficacy towards CB₂

! Type

! References

|-

! Anandamide

| 78nM

| Partial agonist

| 370nM

| ?

| Endogenous

|

|-

! N-Arachidonoyl dopamine

| ?

| Agonist

| ?

| ?

| Endogenous

|

|-

! 2-Arachidonoylglycerol

| ?

| Full agonist

| ?

| ?

| Endogenous

|

|-

! 2-Arachidonyl glyceryl ether

| 21 nM

| Full agonist

| 480nM

| Full agonist

| Endogenous

|

|-

! Δ-9-Tetrahydrocannabinol

| 10nM

| Partial agonist

| 24nM

| Partial agonist

| Phytogenic

|

|-

! EGCG

| 33,600 nM

| Agonist

| >50,000 nM

| ?

| Phytogenic

|

|-

! Yangonin

| 720 nM

| ?

| >10,000 nM

| ?

| Phytogenic

|

|-

! AM-1221

| 52.3nM

| Agonist

| 0.28nM

| Agonist

| Synthetic

|

|-

! AM-1235

| 1.5nM

| Agonist

| 20.4nM

| Agonist

| Synthetic

|

|-

! AM-2232

| 0.28nM

| Agonist

| 1.48nM

| Agonist

| Synthetic

|

|-

! JWH-007

| 9.0nM

| Agonist

| 2.94nM

| Agonist

| Synthetic

|

|-

! JWH-015

| 383nM

| Agonist

| 13.8nM

| Agonist

| Synthetic

|

</references>

External links