Cannabinoid receptor type 1

CNR1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1LVQ, 1LVR, 2B0Y, 2KOE, 2MZ3, 2MZ2, 2MZA,%%s1LVQ, 1LVR, 2B0Y, 2KOE
Identifiers
Aliases	CNR1, CANN6, CB-R, CB1, CB1A, CB1K5, CB1R, CNR, cannabinoid receptor 1 (brain), cannabinoid receptor 1, cannabinoid CB1 receptor gene
External IDs	MGI: 104615 HomoloGene: 7273 GeneCards: CNR1
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6q15 Start 88,139,864 bp[1] End 88,166,359 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 A5|4 16.28 cM Start 33,924,593 bp[2] End 33,948,831 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • G-protein coupled receptor activity • signal transducer activity • cannabinoid receptor activity • drug binding • protein binding • voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels Cellular component • integral component of membrane • intracellular membrane-bounded organelle • membrane • growth cone • integral component of plasma membrane • axon • membrane raft • plasma membrane • presynaptic membrane • mitochondrion • mitochondrial outer membrane • cell projection • integral component of mitochondrial membrane • presynapse • glutamatergic synapse • GABA-ergic synapse • integral component of presynaptic membrane Biological process • negative regulation of nitric-oxide synthase activity • negative regulation of mast cell activation • glucose homeostasis • response to nutrient • regulation of insulin secretion • negative regulation of blood pressure • adenylate cyclase-modulating G-protein coupled receptor signaling pathway • maternal process involved in female pregnancy • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • response to nicotine • aging • positive regulation of fever generation • memory • negative regulation of action potential • regulation of feeding behavior • negative regulation of ion transport • response to morphine • negative regulation of fatty acid beta-oxidation • response to lipopolysaccharide • positive regulation of blood pressure • regulation of penile erection • regulation of lipid metabolic process • spermatogenesis • positive regulation of neuron projection development • positive regulation of apoptotic process • positive regulation of acute inflammatory response to antigenic stimulus • learning or memory • nociception • negative regulation of dopamine secretion • regulation of synaptic transmission, glutamatergic • response to ethanol • axonal fasciculation • regulation of synaptic transmission, GABAergic • signal transduction • response to cocaine • trans-synaptic signaling by endocannabinoid, modulating synaptic transmission • G-protein coupled receptor signaling pathway • cannabinoid signaling pathway • retrograde trans-synaptic signaling by endocannabinoid • positive regulation of presynaptic cytosolic calcium concentration • induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1268	12801
Ensembl	ENSG00000118432	ENSMUSG00000044288
UniProt	P21554	P47746
RefSeq (mRNA)	NM_001160226 NM_001160258 NM_001160259 NM_001160260 NM_016083 NM_033181 NM_001365869 NM_001365870 NM_001365872 NM_001365874	NM_007726 NM_001355020 NM_001355021
RefSeq (protein)	NP_001153698 NP_001153730 NP_001153731 NP_057167 NP_149421 NP_001352798 NP_001352799 NP_001352801 NP_001352803	NP_031752 NP_001341949 NP_001341950 NP_001352810
Location (UCSC)	Chr 6: 88.14 – 88.17 Mb	Chr 4: 33.92 – 33.95 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Cannabinoid receptor type 1 (CB₁), also known as cannabinoid receptor 1, is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene.^[5] The human CB₁ receptor is expressed in the peripheral nervous system and central nervous system.^[5] It is activated by: endocannabinoids, a group of retrograde neurotransmitters that include anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as the compound THC which is an active ingredient of the psychoactive drug cannabis; and, synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).^[6][7]

The primary endogenous agonist of the human CB₁ receptor is anandamide.^[5]

Contents

• 
  1 Structure
  


• 
  2 Mechanism
  


• 
  3 Expression
  
  
  
  • 
    3.1 Brain
    
    
    
    • 
      3.1.1 Hippocampal formation
      
    
    
    • 
      3.1.2 Basal ganglia
      
    
    
    • 
      3.1.3 Cerebellum and neocortex
      
    
    
    
    
  
  
  • 
    3.2 Spine
    
  
  
  • 
    3.3 Other
    
  
  
  
  


• 
  4 Function
  
  
  
  • 
    4.1 Health and disease
    
  
  
  • 
    4.2 Anxiety response to novelty
    
  
  
  • 
    4.3 Gastrointestinal activity
    
  
  
  • 
    4.4 Cardiovascular activity
    
  
  
  • 
    4.5 Plasticity
    
  
  
  • 
    4.6 Motor control
    
  
  
  • 
    4.7 Drug and behavioral addictions
    
  
  
  • 
    4.8 Olfaction
    
  
  
  
  


• 
  5 Use of antagonists
  


• 
  6 Ligands
  
  
  
  • 
    6.1 Agonists
    
    
    
    • 
      6.1.1 Selective
      
    
    
    • 
      6.1.2 Unspecified efficacy
      
    
    
    • 
      6.1.3 Partial
      
      
      
      • 
        6.1.3.1 Endogenous
        
      
      
      • 
        6.1.3.2 Phyto/synthetic
        
      
      
      
      
    
    
    • 
      6.1.4 Full
      
      
      
      • 
        6.1.4.1 Endogenous
        
      
      
      • 
        6.1.4.2 Phyto/synthetic
        
      
      
      
      
    
    
    • 
      6.1.5 Allosteric agonist
      
    
    
    
    
  
  
  • 
    6.2 Antagonists
    
  
  
  • 
    6.3 Inverse agonists
    
  
  
  • 
    6.4 Allosteric modulators
    
  
  
  
  


• 
  7 Binding affinities
  


• 
  8 Evolution
  


• 
  9 See also
  


• 
  10 References
  


• 
  11 External links
  

Structure

The CB₁ receptor shares the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail.^[8][9] The receptor may exist as a homodimer or form heterodimers or other GPCR oligomers with different classes of G-protein-coupled receptors. Observed heterodimers include A_2A–CB₁, CB₁–D₂, OX₁–CB₁, while many more may only be stable enough to exist in vivo.^[10] The CB₁ receptor possesses an allosteric modulatory binding site.^[11][12]

Mechanism

The CB₁ receptor is a pre-synaptic heteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner.^[13] The CB₁ receptor is activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.

Research suggests that the majority of CB₁ receptors are coupled through G_i/o proteins. Upon activation, CB₁ receptor exhibits its effects mainly through activation of G_i, which decreases intracellular cAMP concentration by inhibiting its production enzyme, adenylate cyclase, and increases mitogen-activated protein kinase (MAP kinase) concentration. Alternatively, in some rare cases CB₁ receptor activation may be coupled to G_s proteins, which stimulate adenylate cyclase.^[10] cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influenced inwardly rectifying potassium channels (=Kir or IRK),^[14] and calcium channels, which are activated by cAMP-dependent interaction with such molecules as protein kinase A (PKA), protein kinase C (PKC), Raf-1, ERK, JNK, p38, c-fos, c-jun, and others.^[15]

In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB₁ receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release.^[16] The relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type.

The CB₁ receptor can also be modulated by allosterically synthetic ligands^[17] in a positive^[18] and negative^[19] manner. In vivo exposure to THC impairs long-term potentiation and leads to a reduction of phosphorylated CREB.^[20]

In summary, CB₁ receptor activity has been found to be coupled to certain ion channels, in the following manner:^[10]

• Positively to inwardly rectifying and A-type outward potassium channels.


• Negatively to D-type outward potassium channels


• Negatively to N-type and P/Q-type calcium channels.

Expression

The CB₁ receptor is encoded by the gene CNR1,^[13] located on human chromosome 6.^[16] Two transcript variants encoding different isoforms have been described for this gene.^[13] CNR1 orthologs^[21] have been identified in most mammals.

The CB₁ receptor is expressed pre-synaptically at both glutaminergic and GABAergic interneurons and, in effect, acts as a neuromodulator to inhibit release of glutamate and GABA.^[16] Repeated administration of receptor agonists may result in receptor internalization and/ or a reduction in receptor protein signalling.^[10]

The inverse agonist MK-9470 makes it possible to produce in vivo images of the distribution of CB₁ receptors in the human brain with positron emission tomography.^[22]

Brain

Cnr1 is widely expressed in all major regions of the postnatal day 14 mouse brain, but is conspicuously absent in much of the thalamus.

CB₁ receptors are expressed most densely in the central nervous system and are largely responsible for mediating the effects of cannabinoid binding in the brain. Endocannabinoids released by a depolarized neuron bind to CB₁ receptors on pre-synaptic glutamatergic and GABAergic neurons, resulting in a respective decrease in either glutamate or GABA release. Limiting glutamate release causes reduced excitation, while limiting GABA release suppresses inhibition, a common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated inhibition, in effect exciting the postsynaptic cell.^[16]

Varying levels of CB₁ expression can be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic and hypothalamic nuclei, and other subcortical regions (e.g., the septal region), cerebellar cortex, and brainstem nuclei (e.g., the periaqueductal gray).^[15]

Hippocampal formation

CB₁mRNA transcripts are abundant in GABAergic interneurons of the hippocampus, indirectly reflecting the expression of these receptors and elucidating the established effect of cannabinoids on memory. These receptors are densely located in cornu ammonis pyramidal cells, which are known to release glutamate. Cannabinoids suppress the induction of LTP and LTD in the hippocampus by inhibiting these glutamatergic neurons. By reducing the concentration of glutamate released below the threshold necessary to depolarize the postynaptic receptor NMDA,^[16] a receptor known to be directly related to the induction of LTP and LTD, cannabinoids are a crucial factor in the selectivity of memory.
These receptors are highly expressed by GABAergic interneurons as well as glutamatergic principal neurons. However, a higher density is found within GABAergic cells.^[23] This means that, although synaptic strength/frequency, and thus potential to induce LTP, is lowered, net hippocampal activity is raised. In addition, CB₁ receptors in the hippocampus indirectly inhibit the release of acetylcholine. This serves as the modulatory axis opposing GABA, decreasing neurotransmitter release. Cannabinoids also likely play an important role in the development of memory through their neonatal promotion of myelin formation, and thus the individual segregation of axons.

Basal ganglia

CB₁ receptors are expressed throughout the basal ganglia and have well-established effects on movement in rodents. As in the hippocampus, these receptors inhibit the release of glutamate or GABA transmitter, resulting in decreased excitation or reduced inhibition based on the cell they are expressed in. Consistent with the variable expression of both excitatory glutamate and inhibitory GABA interneurons in both the basal ganglia's direct and indirect motor loops, synthetic cannabinoids are known to influence this system in a dose-dependent triphasic pattern. Decreased locomotor activity is seen at both higher and lower concentrations of applied cannabinoids, whereas an enhancement of movement may occur upon moderate dosages.^[16] However, these dose-dependent effects have been studied predominately in rodents, and the physiological basis for this triphasic pattern warrants future research in humans. Effects may vary based on the site of cannabinoid application, input from higher cortical centers, and whether drug application is unilateral or bilateral.

Cerebellum and neocortex

The role of the CB₁ receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the cerebellum and neocortex, two regions associated with the coordination and initiation of movement. Research suggests that anandamide is synthesized by Purkinje cells and acts on presynaptic receptors to inhibit glutamate release from granule cells or GABA release from the terminals of basket cells. In the neocortex, these receptors are concentrated on local interneurons in cerebral layers II-III and V-VI.^[16] Compared to rat brains, humans express more CB₁ receptors in the cerebral cortex and amygdala and less in the cerebellum, which may help explain why motor function seems to be more compromised in rats than humans upon cannabinoid application.^[23]

Spine

Many of the documented analgesic effects of cannabinoids are based on the interaction of these compounds with CB₁ receptors on spinal cord interneurons in the superficial levels of the dorsal horn, known for its role in nociceptive processing. In particular, the CB₁ is heavily expressed in layers 1 and 2 of the spinal cord dorsal horn and in lamina 10 by the central canal. Dorsal root ganglion also express these receptors, which target a variety of peripheral terminals involved in nociception. Signals on this track are also transmitted to the periaqueductal gray (PAG) of the midbrain. Endogenous cannabinoids are believed to exhibit an analgesic effect on these receptors by limiting both GABA and glutamate of PAG cells that relate to nociceptive input processing, a hypothesis consistent with the finding that anandamide release in the PAG is increased in response to pain-triggering stimuli.^[16]

Other

CB₁ is expressed on several types of cell in pituitary gland, thyroid gland, and possibly in the adrenal gland.^[15] CB₁ is also expressed in several cells relating to metabolism, such as fat cells, muscle cells, liver cells (and also in the endothelial cells, Kupffer cells and stellate cells of the liver), and in the digestive tract.^[15] It is also expressed in the lungs and the kidney.

CB₁ is present on Leydig cells and human sperms. In females, it is present in the ovaries, oviducts myometrium, decidua, and placenta. It has also been implicated in the proper development of the embryo.^[15]

Function

Health and disease

Several studies have implicated the CB₁ receptor in the maintenance of homeostasis in health and disease. In a rodent neuropathic pain model, increased expression of these receptors was seen in thalamic neurons, the spinal cord, and dorsal root ganglion.^[23] Increased receptor expression has also been found in human hepatocellular carcinoma tumor samples and other human prostate cancer cells. The expression of these receptors is believed to modulate neurotransmitter release in a manner that prevents the development of excessive neuronal activity, reducing pain and other inflammatory symptoms. This finding is consistent with the localization of CB₁ receptors to the terminals of central and peripheral neurons, and the established mediation of both excitatory and inhibitory neurotransmitters acetylcholine, noradrenaline, dopamine, 5-HT, GABA, glutamate, D-aspartate, and cholecystokinin.^[23] Through its primary action as a G_i coupled receptor, CB1 inhibits production of cyclic adenosine monophosphate (cAMP), metabotropically inhibiting all NT release.

Enhanced receptor expression following disease has been found to result in a leftward shift in the log dose-response curve of cannabinol, and also an increase in the size of its maximal effects.^[23]

Anxiety response to novelty

A CB₁ receptor knock-out mouse study examined the effect that these receptors play on exploratory behavior in novel situations. Researchers selectively targeted glutamatergic and GABAergic cortical interneurons and studied results in open field, novel object, and sociability tests. Eliminating glutamatergic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement.^[24] These opposing effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Glutamatergic CB₁receptors not only are responsible for mediating aggression but produce anxiolytic-like function by inhibiting excessive arousal, which prevented the mice from exploring both animate and inanimate objects. In contrast, GABAergic CB₁ receptors appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these results illustrate the regulatory function of the CB₁ receptor on the organism's overall sense of arousal during novel situations and suggest that investigatory drive is associated with impulsive behavior.

Another study found that differential synthesis of anandamide and 2-AG in response to stress mediated beneficial effects of the hypothalamic-pituitary-adrenal axis. These effects were eliminated by the application of the CB₁ antagonist AM251, illustrating that this receptor is essential for modulating the function of the stress response.^[25]

Gastrointestinal activity

Inhibition of gastrointestinal activity has been observed after administration of THC or anandamide. This effect is assumed to be CB₁-mediated, since this receptor is expressed by the peptide hormone cholecystokinin, and application of the CB₁-specific inverse agonist SR 141716A (Rimonabant) blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB₂-mediated component.^[26]

The CB₁ receptor inverse agonist rimonabant has been found to reduce intake of food or sweet solutions in both humans and mice. Targeting this receptor with rimonabant has been found to prevent the THC-induced enhancement of DA release in the nucleus accumbens shell from food, suggesting that these receptors may be involved in determining the hedonic value of food.^[27] In addition, CB1 facilitates ghrelin release, normally happening when the stomach is constricted In the presence of a relatively active system, overeating is promoted. This is the genesis of its appetite-stimulating effects, colloquially called "the munchies."

Cardiovascular activity

Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension.^[28] Anandamide and 2-AG, produced by macrophages and platelets, respectively, may mediate this effect.^[28] A likely candidate for this function is the heterodimer of CB1 and adenosine 2a. Through an opposing mechanism of action (A2A elevates cAMP), together, they may serve to regulate cardiac blood supply, and thus output.

Plasticity

CB1 induction of LTD and STD have been shown in the dorsal striatum, amygdala, prefrontal cortex, ventral tegmental area, and the stria terminalis (BNST).^[29] A recent study compared the endocannabinoid induction of LTD and STD in the bed nucleus of the BNST and striatum. Results found that both short- and long-term effects were dependent on CB₁ receptor activation in the striatum, whereas LTD induction in the BNST relied on TRPV1 receptor. Effects vary based on the endocannabinoid molecule: 2-AG was found to act on presynaptic CB₁ receptors to mediate retrograde short-term depression following activation of L-type calcium currents, whereas anandamide was synthesized after mGluR5 activation and triggered autocrine signalling that induced long-term depression.^[30] These findings demonstrate the CB₁ receptor as a direct mechanism for the brain to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs. mGlu5 forms a heterodimer with A2A, which allows endocannabinoids to regulate their own levels, as they inhibit cAMP production, thus increase free adenosine to agonise A2A. This forms a feedback loop between the positive and negative metabotropic receptors, which can maintain a relatively similar homeostasis with any neuron connected through an electrical synapse.

Motor control

CB₁ receptors are expressed throughout motor regions of the mammalian brain, suggesting that CB₁ has a role in motor control. CB₁ activation has been shown to effect specific kinematic variables in rodents, such as the rate of applied force during lever pressing,^[31] and the amplitude (but not timing) of whisker movements.^[32]

Drug and behavioral addictions

Several recent reviews on CB1 receptors and addiction have indicated that CB1 receptor activation reinstates drug seeking behavior in addicts.^[33][34][35]
In humans, this results from the influence that limbic CB1 receptors have on mesolimbic dopamine neurons, specifically dopamine receptors in the nucleus accumbens.^[35] As a consequence, CB1 receptor antagonists can reduce drug seeking behavior in some addicts.^[33][34][35]

Olfaction

The CB₁ receptor is expressed by a number of neurons that project from the anterior olfactory nucleus to the ipsilateral main olfactory bulb. However, the effects of cannabinoids on synaptic activity in these neurons has not been well-studied and its effects on olfaction warrant further research in rodents.^[16] Cannabinoids are not known to have effects on olfaction in humans. However, as with the rest of the brain, it plays a crucial role in modulation of NT release.

Use of antagonists

Selective CB₁ agonists may be used to isolate the effects of the receptor from the CB₂ receptor, as most cannabinoids and endocannabinoids bind to both receptor types.^[16]CB₁ selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). A substantial number of antagonists of the CB1 receptor have been discovered and characterized. TM38837 has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors.

Ligands

Agonists

• 
  Minocycline^[36]
  


• Dronabinol

Selective

• Epigallocatechin


• Epicatechin


• Kavain


• Yangonin


• 
  Oleamide^[37]
  

Unspecified efficacy

• N-Arachidonoyl dopamine


• Cannabinol


• HU-210


• 11-Hydroxy-THC


• Levonantradol

Partial

Endogenous

• 2-Arachidonyl glyceryl ether

Phyto/synthetic

• JWH-073


• Tetrahydrocannabinol

Full

Endogenous

• 2-Arachidonoylglycerol

Phyto/synthetic

• AM-2201


• CP 55,940


• JWH-018


• WIN 55,212-2

Allosteric agonist

• GAT228^[38]
  

Antagonists

• Cannabigerol


• Ibipinabant


• Otenabant


• Tetrahydrocannabivarin


• 
  Virodhamine (Endogenous CB1 antagonist and CB2 agonist)

Inverse agonists

• Rimonabant


• Taranabant

Allosteric modulators

• 
  Lipoxin A4 – endogenous, PAM


• 
  ZCZ-011 – PAM


• 
  Pregnenolone – endogenous, NAM


• 
  Cannabidiol – NAM^[23]
  


• 
  Fenofibrate – NAM


• 
  GAT100 – NAM


• 
  PSNCBAM-1 – NAM


• 
  RVD-Hpα – NAM

Binding affinities

	CB1 affinity (Ki)	Efficacy towards CB1	CB2 affinity (Ki)	Efficacy towards CB2	Type	References
Anandamide	78 nM	Partial agonist	370 nM	Partial agonist	Endogenous
N-Arachidonoyl dopamine	250 nM	Agonist	12000 nM	?	Endogenous	[39]
2-Arachidonoylglycerol	58.3 nM	Full agonist	145 nM	Full agonist	Endogenous	[39]
2-Arachidonyl glyceryl ether	21 nM	Full agonist	480 nM	Full agonist	Endogenous
Tetrahydrocannabinol	10 nM	Partial agonist	24 nM	Partial agonist	Phytogenic	[40][40]
EGCG	33.6 μM	Agonist	>50 μM	?	Phytogenic
AM-1221	52.3 nM	Agonist	0.28 nM	Agonist	Synthetic	[41]
AM-1235	1.5 nM	Agonist	20.4 nM	Agonist	Synthetic	[42]
AM-2232	0.28 nM	Agonist	1.48 nM	Agonist	Synthetic	[42]
UR-144	150 nM	Full agonist	1.8 nM	Full agonist	Synthetic	[43]
JWH-007	9.0 nM	Agonist	2.94 nM	Agonist	Synthetic	[44]
JWH-015	383 nM	Agonist	13.8 nM	Agonist	Synthetic	[44]
JWH-018	9.00 ± 5.00 nM	Full agonist	2.94 ± 2.65 nM	Full agonist	Synthetic	[45]

Evolution

The CNR1 gene is used in animals as a nuclear DNA phylogenetic marker.^[21] This intronless gene has first been used to explore the phylogeny of the major groups of mammals,^[46] and contributed to reveal that placental orders are distributed into five major clades: Xenarthra, Afrotheria, Laurasiatheria, Euarchonta, and Glires. CNR1 has also proven useful at lower taxonomic levels, such as rodents,^[47][48] and for the identification of dermopterans as the closest primate relatives.^[49]

See also

• Discovery and development of Cannabinoid Receptor 1 Antagonists


• Cannabinoid receptor


• 
  Cannabinoid receptor type 2 (CB₂)

References

1. 
   ^ ^abc GRCh38: Ensembl release 89: ENSG00000118432 - Ensembl, May 2017
   


2. 
   ^ ^abc GRCm38: Ensembl release 89: ENSMUSG00000044288 - Ensembl, May 2017
   


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9. 
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External links

• 
  "Cannabinoid Receptors: CB₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
  

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

v t e Cell surface receptor: G protein-coupled receptors
Class A: Rhodopsin-like Neurotransmitter Adrenergic α1 (A B D) α2 (A B C) β1 β2 β3 Purinergic Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14) Serotonin (all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7) Other Acetylcholine (M1 M2 M3 M4 M5) Dopamine D1 D2 D3 D4 D5 GHB receptor Histamine H1 H2 H3 H4 Melatonin (1A 1B 1C) TAAR (1 2 5 6 8 9) Metabolites and signaling molecules Eicosanoid CysLT (1 2) LTB4 1 2 FPRL1 OXE Prostaglandin DP (1 2), EP (1 2 3 4), FP Prostacyclin Thromboxane Other Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Hydroxycarboxylic acids 1 2 3 Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate Peptide Neuropeptide B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2) Other Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin A B Formyl peptide (1 2 3) FSH Galanin (1 2 3) Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2) Miscellaneous Orphan GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183) Other Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)
Class B: Secretin-like Adhesion ADGRG (1 2 3 4 5 6 7) Orphan GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157) Other Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth-hormone-releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)
Class C: Metabotropic glutamate / pheromone Taste TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60 Vomeronasal receptor) Other Calcium-sensing receptor GABAB (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)
Class F: Frizzled & Smoothened Frizzled Frizzled (1 2 3 4 5 6 7 8 9 10) Smoothened Smoothened

v t e Cannabinoid receptor modulators
Receptor (ligands)	CB1 Agonists (abridged; see here for more): 2-AG 2-AGE (noladin ether) 11-Hydroxy-THC α-Amyrin β-Amyrin AB-CHMINACA AM-1172 AM-1220 AM-1221 AM-1235 AM-2201 AM-2232 Anandamide Arvanil AZ-11713908 Cannabinol CB-13 CP 47,497 CP 55,940 Dimethylheptylpyran DEA ECG EGCG Epicatechin Gallocatechol (gallocatechin) Honokiol HU-210 JWH-007 JWH-015 JWH-018 JWH-073 Kavain L-759,633 Levonantradol Menabitan Nabilone Nabitan NADA O-1812 Oleamide Pravadoline Serinolamide A THC (dronabinol) UR-144 WIN 55,212-2 Yangonin Antagonists: AM-251 AM-6545 Cannabidiol Cannabigerol Drinabant Falcarinol (carotatoxin) Hemopressin Ibipinabant LY-320,135 MK-9470 NESS-0327 O-2050 Otenabant PF-514273 PipISB Rimonabant Rosonabant Surinabant Taranabant THCV TM-38837 VCHSR Virodhamine Antibodies: Brizantin (Бризантин) Dietressa (Диетресса) Unknown/unsorted: MAFP CB2 Agonists: 2-AG 2-AGE (noladin ether) 3,3'-Diindolylmethane 4-O-Methylhonokiol α-Amyrin β-Amyrin A-796,260 A-834,735 A-836,339 AM-1172 AM-1221 AM-1235 AM-1241 AM-2232 Anandamide AZ-11713908 Cannabinol Caryophyllene CB-13 CBS-0550 CP-55,940 GW-405,833 (L-768,242) GW-842,166X HU-308 JTE 7-31 JWH-007 JWH-015 JWH-018 JWH-73 JWH-133 L-759,633 L-759,656 Lenabasum (anabasum) Magnolol MDA-19 Nabitan NADA Olorinab (APD-371) PF-03550096 S-444,823 SER-601 Serinolamide A UR-144 Tedalinab THC (dronabinol) THCV Tetrahydromagnolol Virodhamine Antagonists: 4-O-Methylhonokiol AM-630 BML-190 Cannabidiol Honokiol JTE-907 SR-144,528 WIN 54,461 WIN 56,098 NAGly (GPR18) Agonists: Abnormal cannabidiol ACPA AM251 Anandamide Cannabidiol NADGly THC (dronabinol) O-1602 Antagonists: CID-85469571 O-1918 GPR55 Agonists: 2-AGE (noladin ether) 2-ALPI Abnormal cannabidiol AM-251 CID1011163 CID1252842 CID1792579 CP 55,940 GSK-494581A Lysophosphatidylinositol ML-184 ML-185 ML-186 O-1602 Oleoylethanolamide Palmitoylethanolamide THC (dronabinol) Antagonists: Cannabidiol CID-16020046 ML-191 ML-192 ML-193 O-1918 PSB-SB-487 PSB-SB-1202 PSB-SB-1203 Tetrahydromagnolol GPR119 Agonists: 2-Oleoylglycerol Anandamide APD668 AR-231,453 AS-1269574 MBX-2982 N-Oleoyldopamine Oleoylethanolamide Olvanil PSN-375,963 PSN-632,408 Unsorted Agonists: Revosimeline
Transporter (modulators)	eCBTs Inhibitors: 5'-DMH-CBD AM-404 AM-1172 Arachidonoyl serotonin Arvanil Cannabidiol Guineensine LY-2183240 O-2093 OMDM-2 Paracetamol (acetaminophen) SB-FI-26 UCM-707 URB-597 VDM-11 WOBE490 WOBE491 WOBE492
Enzyme (modulators)	FAAH Inhibitors: 4-Nonylphenylboronic acid AACOCF3 AM-404 Arachidonoyl serotonin BIA 10-2474 Biochanin A Genistein IDFP JNJ-1661010 JNJ-42165279 JZL-195 Kaempferol LY-2183240 MAFP Palmitoylisopropylamide Paracetamol (acetaminophen) PF-3845 PF-04457845 PF-750 SA-47 SA-57 TAK 21d TC-F 2 UCM710 URB-597 Activators: PDP-EA MAGL Inhibitors: ABX-1431 IDFP JJKK 048 JW 642 JZL-184 JZL-195 JZP-361 KML 29 MAFP MJN110 NAM Pristimerin URB-602 ABHD6 Inhibitors: JZP-169 JZP-430 KT182 KT185 KT195 KT203 LEI-106 ML294 ML295 ML296 UCM710 WWL-70 ABHD12 Inhibitors: Betulinic acid Maslinic acid MAFP Oleanolic acid Orlistat (tetrahydrolipstatin) Ursolic acid
Others	Precursors: Phosphatidylethanolamine NAPE Diacylglycerol Others: 2-PG (directly potentiates activity of 2-AG at CB1 receptor) ARN-272 (FAAH-like anandamide transporter inhibitor)
See also Receptor/signaling modulators Cannabinoids (cannabinoids by structure)

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