Cannabinoid receptor type 2

"CNR2" redirects here. For the airport in Ontario, Canada, see Innerkip Aerodrome.

CNR2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KI9
Identifiers
Aliases	CNR2, CB-2, CB2, CX5, Cannabinoid receptor type 2, cannabinoid receptor 2
External IDs	MGI: 104650 HomoloGene: 1389 GeneCards: CNR2
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.11 Start 23,870,526 bp[1] End 23,913,362 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 D3 Start 135,895,394 bp[2] End 135,920,207 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • G-protein coupled receptor activity • signal transducer activity • cannabinoid receptor activity Cellular component • integral component of membrane • perikaryon • cell projection • membrane • extrinsic component of cytoplasmic side of plasma membrane • plasma membrane • integral component of plasma membrane • neuronal cell body • dendrite • neuron projection Biological process • negative regulation of nitric-oxide synthase activity • negative regulation of mast cell activation • cannabinoid signaling pathway • response to amphetamine • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • negative regulation of action potential • response to lipopolysaccharide • negative regulation of synaptic transmission, GABAergic • immune response • nociception • inflammatory response • negative regulation of inflammatory response • signal transduction • leukocyte chemotaxis • G-protein coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1269	12802
Ensembl	ENSG00000188822	ENSMUSG00000062585
UniProt	P34972	P47936
RefSeq (mRNA)	NM_001841	NM_009924 NM_001305278
RefSeq (protein)	NP_001832	NP_001292207 NP_034054
Location (UCSC)	Chr 1: 23.87 – 23.91 Mb	Chr 4: 135.9 – 135.92 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

The cannabinoid receptor type 2, abbreviated as CB₂, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene.^[5][6] It is closely related to the cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol, the active agent in cannabis, and other phytocannabinoids (plant cannabinoids).^[5][7] The principal endogenous ligand for the CB₂ receptor is 2-arachidonoylglycerol (2-AG).^[6]

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.^[5] The receptor was identified among cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor type 1 (CB₁) receptor, discovered in 1990.^[8] The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system.

Contents

• 
  1 Structure
  


• 
  2 Mechanism
  


• 
  3 Expression
  
  
  
  • 
    3.1 Dispute
    
  
  
  • 
    3.2 Immune system
    
  
  
  • 
    3.3 Brain
    
  
  
  • 
    3.4 Gastrointestinal system
    
  
  
  • 
    3.5 Peripheral nervous system
    
  
  
  
  


• 
  4 Function
  
  
  
  • 
    4.1 Immune system
    
  
  
  • 
    4.2 Clinical applications
    
  
  
  • 
    4.3 Modulation of cocaine reward
    
  
  
  
  


• 
  5 Ligands
  
  
  
  • 
    5.1 Agonists
    
  
  
  • 
    5.2 Partial agonists
    
  
  
  • 
    5.3 Unspecified efficacy agonists
    
    
    
    • 
      5.3.1 Herbal
      
    
    
    
    
  
  
  • 
    5.4 Inverse agonists
    
  
  
  
  


• 
  6 Binding affinities
  


• 
  7 See also
  


• 
  8 References
  


• 
  9 Further reading
  


• 
  10 External links
  

Structure

The CB₂ receptor is encoded by the CNR2 gene.^[5][9] Approximately 360 amino acids comprise the human CB₂ receptor, making it somewhat shorter than the 473-amino-acid-long CB₁ receptor.^[9]

As is commonly seen in G protein-coupled receptors, the CB₂ receptor has seven transmembrane spanning domains,^[10] a glycosylated N-terminus, and an intracellular C-terminus.^[9] The C-terminus of CB₂ receptors appears to play a critical role in the regulation of ligand-induced receptor desensitization and downregulation following repeated agonist application,^[9] perhaps causing the receptor to become less responsive to particular ligands.

The human CB₁ and the CB₂ receptors possess approximately 44% amino acid similarity.^[5] When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%.^[9] The amino acid sequence of the CB₂ receptor is less highly conserved across human and rodent species as compared to the amino acid sequence of the CB₁ receptor.^[11] Based on computer modeling, ligand interactions with CB₂ receptor residues S3.31 and F5.46 appears to determine differences between CB₁ and CB₂ receptor selectivity.^[12] In CB₂ receptors, lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue.^[12] These interactions induce a conformational change in the receptor structure, which triggers the activation of various intracellular signaling pathways. Further research is needed to determine the exact molecular mechanisms of signaling pathway activation.^[12]

Mechanism

Like the CB₁ receptors, CB₂ receptors inhibit the activity of adenylyl cyclase through their Gi/Go_α subunits.^[13][14] Through their G_βγ subunits, CB₂ receptors are also known to be coupled to the MAPK-ERK pathway,^[13][14][15] a complex and highly conserved signal transduction pathway, which critically regulates a number of important cellular processes in both mature and developing tissues.^[16] Activation of the MAPK-ERK pathway by CB₂ receptor agonists acting through the G_βγ subunit ultimately results in changes in cell migration^[17] as well as in an induction of the growth-related gene Zif268 (also known as Krox-24, NGFI-A, and egr-1).^[15] The Zifi268 gene encodes a transcriptional regulator implicated in neuroplasticity and long term memory formation.^[18]

At present, there are five recognized cannabinoids produced endogenously throughout the body: Arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine,^[13] as well as the recently discovered N-arachidonoyl-dopamine (NADA).^[19] Many of these ligands appear to exhibit properties of functional selectivity at the CB₂ receptor: 2-AG preferentially activates the MAPK-ERK pathway, while noladin preferentially inhibits adenylyl cyclase.^[13] Like noladin, the synthetic ligand CP-55,940 has also been shown to preferentially inhibit adenylyl cyclase in CB₂ receptors.^[13] Together, these results support the emerging concept of agonist-directed trafficking at the cannabinoid receptors.

Expression

Dispute

Originally it was thought that the CB2 receptor was only expressed in peripheral tissue while the CB1 receptor is the endogenous receptor on neurons. Recent work with immunohistochemical staining has shown expression within neurons. Subsequently, it was shown that CB2 knock out mice, produced the same immunohistochemical staining, indicating the presence of the CB2 receptor where none was expressed. This has created a long history of debate as to the Central Nervous System expression of the CB2 receptor. A new mouse model was described in 2014 that expresses a fluorescent protein whenever CB2 is expressed within a cell. This has the potential to resolve questions about the expression of CB2 receptors in various tissues.^[20]

Immune system

Initial investigation of CB₂ receptor expression patterns focused on the presence of CB₂ receptors in the peripheral tissues of the immune system ^[10] and found CB₂ receptor mRNA is found throughout tissues of the spleen, tonsils, and thymus gland.^[10]Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues,^[10] where they are primarily responsible for mediating cytokine release.^[21] These receptors were primarily localized on immune cells such as monocytes, macrophages, B-cells, and T-cells.^{[6][10][22][23][24]}

Brain

Further investigation into the expression patterns of the CB₂ receptors revealed that CB₂ receptor gene transcripts are also expressed in the brain, though not as densely as the CB₁ receptor and located on different cells.^[25] Unlike the CB₁ receptor, in the brain, CB₂ receptors are found primarily on microglia.^[21][26] The CB₂ receptor is expressed in some neurons within the central nervous system (e.g.; the brainstem), but the expression is very low.^[27][28] CB2Rs are expressed on some rat retinal cell types.^[29] Functional CB₂ receptors are expressed in neurons of the ventral tegmental area and the hippocampus, arguing for a widespread expression and functional relevance in the CNS and in particular in neuronal signal transmission.^[30][31]

Gastrointestinal system

CB₂ receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response.^[32][33] Thus, CB₂ receptor is a potential therapeutic target for inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis.^[33][34] The role of endocannabinoids, as such, play an important role in inhibiting unnecessary immune action upon the natural gut flora. Dysfunction of this system, perhaps from excess FAAH activity, could result in IBD. CB₂ activation may also have a role in the treatment of irritable bowel syndrome.^[35] Cannabinoid receptor agonists reduce gut motility in IBS patients.^[36]

Peripheral nervous system

Application of CB₂-specific antagonists has found that these receptors are also involved in mediating analgesic effects in the peripheral nervous system. However, these receptors are not expressed by nociceptive sensory neurons, and at present are believed to exist on an undetermined, non-neuronal cell. Possible candidates include mast cells, known to facilitate the inflammatory response. Cannabinoid mediated inhibition of these responses may cause a decrease in the perception of noxious-stimuli.^[8]

Function

Immune system

Primary research on the functioning of the CB₂ receptor has focused on the receptor's effects on the immunological activity of leukocytes.^[37] To be specific, this receptor has been implicated in a variety of modulatory functions, including immune suppression, induction of apoptosis, and induction of cell migration.^[6] Through their inhibition of adenylyl cyclase via their Gi/Go_α subunits, CB₂ receptor agonists cause a reduction in the intracellular levels of cyclic adenosine monophosphate (cAMP).^[38][39] Although the exact role of the cAMP cascade in the regulation of immune responses is currently under debate, laboratories have previously demonstrated that inhibition of adenylyl cyclase by CB₂ receptor agonists results in a reduction in the binding of transcription factor CREB (cAMP response element-binding protein) to DNA.^[37] This reduction causes changes in the expression of critical immunoregulatory genes^[38] and ultimately suppression of immune function.^[39]

Later studies examining the effect of synthetic cannabinoid agonist JWH-015 on CB₂ receptors revealed that changes in cAMP levels result in the phosphorylation of leukocyte receptor tyrosine kinase at Tyr-505, leading to an inhibition of T cell receptor signaling. Thus, CB₂ agonists may also be useful for treatment of inflammation and pain, and are currently being investigated, in particular for forms of pain that do not respond well to conventional treatments, such as neuropathic pain.^[40] Consistent with these findings are studies that demonstrate increased CB₂ receptor expression in the spinal cord, dorsal root ganglion, and activated microglia in the rodent neuropathic pain model, as well as on human heptocellular carcinoma tumor samples.^[41]

CB₂ receptors have also been implicated in the regulation of homing and retention of marginal zone B cells. A study using knock-out mice found that CB₂ receptor is essential for the maintenance of both MZ B cells and their precursor T2-MZP, though not their development. Both B cells and their precursors lacking this receptor were found in reduced numbers, explained by the secondary finding that 2-AG signaling was demonstrated to induce proper B cell migration to the MZ. Without the receptor, there was an undesirable spike in the blood concentration of MZ B lineage cells and a significant reduction in the production of IgM. While the mechanism behind this process is not fully understood, the researchers suggested that this process may be due to the activation-dependent decrease in cAMP concentration, leading to reduced transcription of genes regulated by CREB, indirectly increasing TCR signaling and IL-2 production.^[6] Together, these findings demonstrate that the endocannabinoid system may be exploited to enhance immunity to certain pathogens and autoimmune diseases.

Clinical applications

CB₂ receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease.^[42][43] Specifically, the CB₂ agonist JWH-015 was shown to induce macrophages to remove native beta-amyloid protein from frozen human tissues.^[44] In patients with Alzheimer's disease, beta-amyloid proteins form aggregates known as senile plaques, which disrupt neural functioning.^[45]

Changes in endocannabinoid levels and/or CB₂ receptor expressions have been reported in almost all diseases affecting humans,^[46] ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer. The prevalence of this trend suggests that modulating CB₂ receptor activity by either selective CB₂ receptor agonists or inverse agonists/antagonists depending on the disease and its progression holds unique therapeutic potential for these pathologies ^[46]

Modulation of cocaine reward

Researchers investigated the effects of CB₂ agonists on cocaine self-administration in mice. Systemic administration of JWH-133 reduced the number of self-infusions of cocaine in mice, as well as reducing locomotor activity and the break point (maximum amount of level presses to obtain cocaine). Local injection of JWH-133 into the nucleus accumbens was found to produce the same effects as systemic administration. Systemic administration of JWH-133 also reduced basal and cocaine-induced elevations of extracellular dopamine in the nucleus accumbens. These findings were mimicked by another, structurally different CB₂ agonist, GW-405,833, and were reversed by the administration of a CB₂ antagonist, AM-630.^[47]

Ligands

Many selective ligands for the CB₂ receptor are now available.^[48]

Agonists

• 
  Minocycline^[49]
  

Partial agonists

• GW-405,833

Unspecified efficacy agonists

• AM-1241


• HU-308


• JWH-015


• JWH-133


• L-759,633


• L-759,656

Herbal

• Echinacea purpurea

Inverse agonists

• AM-630


• BML-190


• JTE-907


• SR-144,528

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	[50]
2-Arachidonoylglycerol	58.3 nM	Full agonist	145 nM	Full agonist	Endogenous	[50]
2-Arachidonyl glyceryl ether	21 nM	Full agonist	480 nM	Full agonist	Endogenous
Tetrahydrocannabinol	10 nM	Partial agonist	24 nM	Partial agonist	Phytogenic	[51][51]
EGCG	33.6 μM	Agonist	>50 μM	?	Phytogenic	[52]
EGC	35.7 μM	Agonist	>50 μM	?	Phytogenic	[52]
ECG	47.3 μM	Agonist	>50 μM	?	Phytogenic	[52]
N-alkylamide	-	-	<100 nM	Partial agonist	Phytogenic	[53][53]
β-Caryophyllene	-	-	<200 nM	Full agonist	Phytogenic	[53]
Falcarinol	<1 μM	Inverse agonist	?	?	Phytogenic	[53]
Rutamarin	-	-	<10 μM	?	Phytogenic	[53]
3,3'-Diindolylmethane	-	-	1 μM	Partial Agonist	Phytogenic	[53]
AM-1221	52.3 nM	Agonist	0.28 nM	Agonist	Synthetic	[54]
AM-1235	1.5 nM	Agonist	20.4 nM	Agonist	Synthetic	[55]
AM-2232	0.28 nM	Agonist	1.48 nM	Agonist	Synthetic	[55]
UR-144	150 nM	Full agonist	1.8 nM	Full agonist	Synthetic	[56]
JWH-007	9.0 nM	Agonist	2.94 nM	Agonist	Synthetic	[57]
JWH-015	383 nM	Agonist	13.8 nM	Agonist	Synthetic	[57]
JWH-018	9.00 ± 5.00 nM	Full agonist	2.94 ± 2.65 nM	Full agonist	Synthetic	[57]

See also

• Cannabinoid receptor


• 
  Cannabinoid receptor type 1 (CB₁)

References

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Further reading

.mw-parser-output .refbegin{font-size:90%;margin-bottom:0.5em}.mw-parser-output .refbegin-hanging-indents>ul{list-style-type:none;margin-left:0}.mw-parser-output .refbegin-hanging-indents>ul>li,.mw-parser-output .refbegin-hanging-indents>dl>dd{margin-left:0;padding-left:3.2em;text-indent:-3.2em;list-style:none}.mw-parser-output .refbegin-100{font-size:100%}

• 
  Oddi S, Spagnuolo P, Bari M, D'Agostino A, Maccarrone M (2007). "Differential modulation of type 1 and type 2 cannabinoid receptors along the neuroimmune axis". International Review of Neurobiology. International Review of Neurobiology. 82: 327–37. doi:10.1016/S0074-7742(07)82017-4. ISBN 978-0-12-373989-6. PMID 17678969.
  


• 
  Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (Aug 1995). "Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations". European Journal of Biochemistry / FEBS. 232 (1): 54–61. doi:10.1111/j.1432-1033.1995.tb20780.x. PMID 7556170.
  


• 
  Munro S, Thomas KL, Abu-Shaar M (Sep 1993). "Molecular characterization of a peripheral receptor for cannabinoids". Nature. 365 (6441): 61–5. doi:10.1038/365061a0. PMID 7689702.
  


• 
  Shire D, Calandra B, Rinaldi-Carmona M, Oustric D, Pessègue B, Bonnin-Cabanne O, Le Fur G, Caput D, Ferrara P (Jun 1996). "Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor". Biochimica et Biophysica Acta. 1307 (2): 132–6. doi:10.1016/0167-4781(96)00047-4. PMID 8679694.
  


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  Tao Q, McAllister SD, Andreassi J, Nowell KW, Cabral GA, Hurst DP, Bachtel K, Ekman MC, Reggio PH, Abood ME (Mar 1999). "Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity". Molecular Pharmacology. 55 (3): 605–13. PMID 10051546.
  


• 
  Nong L, Newton C, Friedman H, Klein TW (2002). "CB1 and CB2 receptor mRNA expression in human peripheral blood mononuclear cells (PBMC) from various donor types". In Friedman H, Klein TW, Madden JJ. Neuroimmune Circuits, Drugs of Abuse, and Infectious Diseases. Advances in Experimental Medicine and Biology. 493. pp. 229–33. doi:10.1007/0-306-47611-8_27. ISBN 0-306-46466-7. PMID 11727770.
  


• 
  Ho BY, Current L, Drewett JG (Jul 2002). "Role of intracellular loops of cannabinoid CB(1) receptor in functional interaction with G(alpha16)". FEBS Letters. 522 (1–3): 130–4. doi:10.1016/S0014-5793(02)02917-4. PMID 12095632.
  


• 
  Matias I, Pochard P, Orlando P, Salzet M, Pestel J, Di Marzo V (Aug 2002). "Presence and regulation of the endocannabinoid system in human dendritic cells". European Journal of Biochemistry / FEBS. 269 (15): 3771–8. doi:10.1046/j.1432-1033.2002.03078.x. PMID 12153574.
  


• 
  Song ZH, Feng W (Nov 2002). "Absence of a conserved proline and presence of a conserved tyrosine in the CB2 cannabinoid receptor are crucial for its function". FEBS Letters. 531 (2): 290–4. doi:10.1016/S0014-5793(02)03537-8. PMID 12417328.
  


• 
  Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, Jorcano JL, Guzmán M (Jan 2003). "Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors". The Journal of Clinical Investigation. 111 (1): 43–50. doi:10.1172/JCI16116. PMC 151833. PMID 12511587.
  


• 
  Feng W, Song ZH (Apr 2003). "Effects of D3.49A, R3.50A, and A6.34E mutations on ligand binding and activation of the cannabinoid-2 (CB2) receptor". Biochemical Pharmacology. 65 (7): 1077–85. doi:10.1016/S0006-2952(03)00005-4. PMID 12663043.
  


• 
  Kishimoto S, Gokoh M, Oka S, Muramatsu M, Kajiwara T, Waku K, Sugiura T (Jul 2003). "2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism". The Journal of Biological Chemistry. 278 (27): 24469–75. doi:10.1074/jbc.M301359200. PMID 12711605.
  


• 
  Jorda MA, Rayman N, Valk P, De Wee E, Delwel R (May 2003). "Identification, characterization, and function of a novel oncogene: the peripheral cannabinoid receptor Cb2". Annals of the New York Academy of Sciences. 996: 10–6. doi:10.1111/j.1749-6632.2003.tb03227.x. PMID 12799277.
  


• 
  Rayman N, Lam KH, Laman JD, Simons PJ, Löwenberg B, Sonneveld P, Delwel R (Feb 2004). "Distinct expression profiles of the peripheral cannabinoid receptor in lymphoid tissues depending on receptor activation status". Journal of Immunology. 172 (4): 2111–7. doi:10.4049/jimmunol.172.4.2111. PMID 14764676.
  


• 
  Rao GK, Zhang W, Kaminski NE (May 2004). "Cannabinoid receptor-mediated regulation of intracellular calcium by delta(9)-tetrahydrocannabinol in resting T cells". Journal of Leukocyte Biology. 75 (5): 884–92. doi:10.1189/jlb.1203638. PMID 14966196.
  


• 
  Alberich Jordà M, Rayman N, Tas M, Verbakel SE, Battista N, van Lom K, Löwenberg B, Maccarrone M, Delwel R (Jul 2004). "The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner". Blood. 104 (2): 526–34. doi:10.1182/blood-2003-12-4357. PMID 15039279.
  


• 
  Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, Tolón RM, Romero J (Sep 2004). "Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study". Synapse. 53 (4): 208–13. doi:10.1002/syn.20050. PMID 15266552.
  


• 
  Gokoh M, Kishimoto S, Oka S, Mori M, Waku K, Ishima Y, Sugiura T (Mar 2005). "2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces rapid actin polymerization in HL-60 cells differentiated into macrophage-like cells". The Biochemical Journal. 386 (Pt 3): 583–9. doi:10.1042/BJ20041163. PMC 1134878. PMID 15456404.
  


• 
  Miller, A. M.; Stella, N. (2008). "CB2receptor-mediated migration of immune cells: it can go either way". British Journal of Pharmacology. 153 (2): 299–308. doi:10.1038/sj.bjp.0707523. PMC 2219538. PMID 17982478.
  


• 
  López EM, Tagliaferro P, Onaivi ES, López-Costa JJ (May 2011). "Distribution of CB2 cannabinoid receptor in adult rat retina". Synapse. 65 (5): 388–92. doi:10.1002/syn.20856. PMID 20803619.
  

External links

• 
  "Cannabinoid Receptors: CB₂". 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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