Cannabinoid receptor type 2
|, CB-2, CB2, CX5, Cannabinoid receptor type 2, cannabinoid receptor 2|
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. It is closely related to the cannabinoid receptor type 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 type 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.
As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains, a glycosylated N-terminus, and an intracellular C-terminus. 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, perhaps causing the receptor to become less responsive to particular ligands.
The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity. When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%. 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. 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. In CB2 receptors, lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue. 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.
Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits. CB2 can also couple to stimulatory Gαs subunits leading to an increase of intracellular cAMP, as has been shown for human leukocytes. Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK-ERK pathway, a complex and highly conserved signal transduction pathway, which regulates a number of cellular processes in mature and developing tissues. Activation of the MAPK-ERK pathway by CB2 receptor agonists acting through the Gβγ subunit ultimately results in changes in cell migration.
Five recognized cannabinoids are produced endogenously: arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine, as well as N-arachidonoyl-dopamine (NADA). Many of these ligands appear to exhibit properties of functional selectivity at the CB2 receptor: 2-AG activates the MAPK-ERK pathway, while noladin inhibits adenylyl cyclase.
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.
Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system, and found the CB2 receptor mRNA in the spleen, tonsils, and thymus gland. CB2 expression in human peripheral blood mononuclear cells at protein level has been confirmed by whole cell radioligand binding. Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues, where they are primarily responsible for mediating cytokine release. These receptors were localized on immune cells such as monocytes, macrophages, B-cells, and T-cells.
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. Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on microglia. The CB2 receptor is expressed in some neurons within the central nervous system (e.g.; the brainstem), but the expression is very low. CB2Rs are expressed on some rat retinal cell types. 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.
CB2 receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response. Thus, CB2 receptor is a potential therapeutic target for inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. 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. Cannabinoid receptor agonists reduce gut motility in IBS patients.
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.
Primary research on the functioning of the CB2 receptor has focused on the receptor's effects on the immunological activity of leukocytes. 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. Through their inhibition of adenylyl cyclase via their Gi/Goα subunits, CB2 receptor agonists cause a reduction in the intracellular levels of cyclic adenosine monophosphate (cAMP). CB2 also signals via Gαs and increases intracellular cAMP in human leukocytes, leading to induction of interleukins 6 and 10. 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. This reduction causes changes in the expression of critical immunoregulatory genes and ultimately suppression of immune function.
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. 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.
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. Together, these findings demonstrate that the endocannabinoid system may be exploited to enhance immunity to certain pathogens and autoimmune diseases.
CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease. Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native beta-amyloid protein from frozen human tissues. In patients with Alzheimer's disease, beta-amyloid proteins form aggregates known as senile plaques, which disrupt neural functioning.
Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, 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 
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.
Many selective ligands for the CB2 receptor are now available.
Unspecified efficacy agonists
|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|||
|2-Arachidonoylglycerol||58.3 nM||Full agonist||145 nM||Full agonist||Endogenous|||
|2-Arachidonyl glyceryl ether||21 nM||Full agonist||480 nM||Full agonist||Endogenous|
|Tetrahydrocannabinol||10 nM||Partial agonist||24 nM||Partial agonist||Phytogenic|||
|EGCG||33.6 μM||Agonist||>50 μM||?||Phytogenic|||
|EGC||35.7 μM||Agonist||>50 μM||?||Phytogenic|||
|ECG||47.3 μM||Agonist||>50 μM||?||Phytogenic|||
|N-alkylamide||-||-||<100 nM||Partial agonist||Phytogenic|||
|β-Caryophyllene||-||-||<200 nM||Full agonist||Phytogenic|||
|Falcarinol||<1 μM||Inverse agonist||?||?||Phytogenic|||
|3,3'-Diindolylmethane||-||-||1 μM||Partial Agonist||Phytogenic|||
|AM-1221||52.3 nM||Agonist||0.28 nM||Agonist||Synthetic|||
|AM-1235||1.5 nM||Agonist||20.4 nM||Agonist||Synthetic|||
|AM-2232||0.28 nM||Agonist||1.48 nM||Agonist||Synthetic|||
|UR-144||150 nM||Full agonist||1.8 nM||Full agonist||Synthetic|||
|JWH-007||9.0 nM||Agonist||2.94 nM||Agonist||Synthetic|||
|JWH-015||383 nM||Agonist||13.8 nM||Agonist||Synthetic|||
|JWH-018||9.00 ± 5.00 nM||Full agonist||2.94 ± 2.65 nM||Full agonist||Synthetic|||
- GRCh38: Ensembl release 89: ENSG00000188822 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000062585 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Munro S, Thomas KL, Abu-Shaar M (September 1993). "Molecular characterization of a peripheral receptor for cannabinoids". Nature. 365 (6441): 61–5. Bibcode:1993Natur.365...61M. doi:10.1038/365061a0. PMID 7689702. S2CID 4349125.
- Basu S, Ray A, Dittel BN (December 2011). "Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses". Journal of Immunology. 187 (11): 5720–32. doi:10.4049/jimmunol.1102195. PMC 3226756. PMID 22048769.
- "Entrez Gene: CNR2 cannabinoid receptor 2 (macrophage)".
- Elphick MR, Egertová M (March 2001). "The neurobiology and evolution of cannabinoid signalling". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 356 (1407): 381–408. doi:10.1098/rstb.2000.0787. PMC 1088434. PMID 11316486.
- Cabral GA, Griffin-Thomas L (January 2009). "Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation". Expert Reviews in Molecular Medicine. 11: e3. doi:10.1017/S1462399409000957. PMC 2768535. PMID 19152719.
- Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, et al. (August 1995). "Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations". European Journal of Biochemistry. 232 (1): 54–61. doi:10.1111/j.1432-1033.1995.tb20780.x. PMID 7556170.
- Griffin G, Tao Q, Abood ME (March 2000). "Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor". The Journal of Pharmacology and Experimental Therapeutics. 292 (3): 886–94. PMID 10688601.
- Tuccinardi T, Ferrarini PL, Manera C, Ortore G, Saccomanni G, Martinelli A (February 2006). "Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis". Journal of Medicinal Chemistry. 49 (3): 984–94. doi:10.1021/jm050875u. PMID 16451064.
- Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL (November 2005). "Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors". The Journal of Pharmacology and Experimental Therapeutics. 315 (2): 828–38. doi:10.1124/jpet.105.089474. PMID 16081674. S2CID 2759320.
- Demuth DG, Molleman A (January 2006). "Cannabinoid signalling". Life Sciences. 78 (6): 549–63. doi:10.1016/j.lfs.2005.05.055. PMID 16109430.
- Saroz, Yurii; Kho, Dan T.; Glass, Michelle; Graham, Euan Scott; Grimsey, Natasha Lillia (2019-10-19). "Cannabinoid Receptor 2 (CB 2 ) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes". ACS Pharmacology & Translational Science. 2 (6): 414–428. doi:10.1021/acsptsci.9b00049. ISSN 2575-9108. PMC 7088898. PMID 32259074.
- Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrié B, Rinaldi-Carmona M, et al. (May 1996). "Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression". European Journal of Biochemistry. 237 (3): 704–11. doi:10.1111/j.1432-1033.1996.0704p.x. PMID 8647116.
- Shvartsman SY, Coppey M, Berezhkovskii AM (2009). "MAPK signaling in equations and embryos". Fly. 3 (1): 62–7. doi:10.4161/fly.3.1.7776. PMC 2712890. PMID 19182542.
- Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA (April 1997). "Regulation of cell motility by mitogen-activated protein kinase". The Journal of Cell Biology. 137 (2): 481–92. doi:10.1083/jcb.137.2.481. PMC 2139771. PMID 9128257.
- Bisogno T, Melck D, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V (November 2000). "N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo". The Biochemical Journal. 351 (3): 817–24. doi:10.1042/bj3510817. PMC 1221424. PMID 11042139.
- Rogers N (September 2015). "Cannabinoid receptor with an 'identity crisis' gets a second look". Nature Medicine. 21 (9): 966–7. doi:10.1038/nm0915-966. PMID 26340113. S2CID 205382482.
- Pertwee RG (April 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview". International Journal of Obesity. 30 Suppl 1: S13-8. doi:10.1038/sj.ijo.0803272. PMID 16570099.
- Onaivi ES (2006). "Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain". Neuropsychobiology. 54 (4): 231–46. doi:10.1159/000100778. PMID 17356307.
- Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F (January 2008). "CB2 receptors in the brain: role in central immune function". British Journal of Pharmacology. 153 (2): 240–51. doi:10.1038/sj.bjp.0707584. PMC 2219530. PMID 18037916.
- Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. (October 2005). "Identification and functional characterization of brainstem cannabinoid CB2 receptors". Science. 310 (5746): 329–32. Bibcode:2005Sci...310..329V. doi:10.1126/science.1115740. PMID 16224028. S2CID 33075917.
- Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR (February 2006). "Cannabinoid CB2 receptors: immunohistochemical localization in rat brain". Brain Research. 1071 (1): 10–23. doi:10.1016/j.brainres.2005.11.035. PMID 16472786. S2CID 25442161.
- 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. S2CID 206520909.
- Zhang HY, Gao M, Shen H, Bi GH, Yang HJ, Liu QR, et al. (May 2017). "2 receptor in VTA dopamine neurons in rats". Addiction Biology. 22 (3): 752–765. doi:10.1111/adb.12367. PMC 4969232. PMID 26833913.
- Stempel AV, Stumpf A, Zhang HY, Özdoğan T, Pannasch U, Theis AK, et al. (May 2016). "Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus". Neuron. 90 (4): 795–809. doi:10.1016/j.neuron.2016.03.034. PMC 5533103. PMID 27133464.
- Izzo AA (August 2004). "Cannabinoids and intestinal motility: welcome to CB2 receptors". British Journal of Pharmacology. 142 (8): 1201–2. doi:10.1038/sj.bjp.0705890. PMC 1575197. PMID 15277313.
- Wright KL, Duncan M, Sharkey KA (January 2008). "Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation". British Journal of Pharmacology. 153 (2): 263–70. doi:10.1038/sj.bjp.0707486. PMC 2219529. PMID 17906675.
- Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, Izzo AA (July 2008). "Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice". British Journal of Pharmacology. 154 (5): 1001–8. doi:10.1038/bjp.2008.177. PMC 2451037. PMID 18469842.
- Storr MA, Yüce B, Andrews CN, Sharkey KA (August 2008). "The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome". Neurogastroenterology and Motility. 20 (8): 857–68. doi:10.1111/j.1365-2982.2008.01175.x. PMID 18710476. S2CID 7045854.
- Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, Zinsmeister AR (November 2011). "Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome". Gastroenterology. 141 (5): 1638–47.e1–7. doi:10.1053/j.gastro.2011.07.036. PMC 3202649. PMID 21803011.
- Kaminski NE (December 1998). "Inhibition of the cAMP signaling cascade via cannabinoid receptors: a putative mechanism of immune modulation by cannabinoid compounds". Toxicology Letters. 102–103: 59–63. doi:10.1016/S0378-4274(98)00284-7. PMID 10022233.
- Herring AC, Koh WS, Kaminski NE (April 1998). "Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and kappaB elements by cannabinol, a minimally CNS-active cannabinoid". Biochemical Pharmacology. 55 (7): 1013–23. doi:10.1016/S0006-2952(97)00630-8. PMID 9605425.
- Kaminski NE (October 1996). "Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression". Biochemical Pharmacology. 52 (8): 1133–40. doi:10.1016/0006-2952(96)00480-7. PMID 8937419.
- Cheng Y, Hitchcock SA (July 2007). "Targeting cannabinoid agonists for inflammatory and neuropathic pain". Expert Opinion on Investigational Drugs. 16 (7): 951–65. doi:10.1517/13543722.214.171.1241. PMID 17594182. S2CID 11159623.
- Pertwee RG (January 2008). "The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin". British Journal of Pharmacology. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532. PMID 17828291.
- Benito C, Núñez E, Tolón RM, Carrier EJ, Rábano A, Hillard CJ, Romero J (December 2003). "Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains". The Journal of Neuroscience. 23 (35): 11136–41. doi:10.1523/JNEUROSCI.23-35-11136.2003. PMC 6741043. PMID 14657172.
- Fernández-Ruiz J, Pazos MR, García-Arencibia M, Sagredo O, Ramos JA (April 2008). "Role of CB2 receptors in neuroprotective effects of cannabinoids" (PDF). Molecular and Cellular Endocrinology. 286 (1–2 Suppl 1): S91-6. doi:10.1016/j.mce.2008.01.001. PMID 18291574. S2CID 33400848.
- Tolón RM, Núñez E, Pazos MR, Benito C, Castillo AI, Martínez-Orgado JA, Romero J (August 2009). "The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages". Brain Research. 1283 (11): 148–54. doi:10.1016/j.brainres.2009.05.098. PMID 19505450. S2CID 195685038.
- Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (June 2004). "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology. 62 (11): 1984–9. doi:10.1212/01.WNL.0000129697.01779.0A. PMID 15184601. S2CID 25017332.
- Pacher P, Mechoulam R (April 2011). "Is lipid signaling through cannabinoid 2 receptors part of a protective system?". Progress in Lipid Research. 50 (2): 193–211. doi:10.1016/j.plipres.2011.01.001. PMC 3062638. PMID 21295074.
- Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, et al. (July 2011). "Brain cannabinoid CB₂ receptors modulate cocaine's actions in mice". Nature Neuroscience. 14 (9): 1160–6. doi:10.1038/nn.2874. PMC 3164946. PMID 21785434.
- Marriott KS, Huffman JW (2008). "Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor". Current Topics in Medicinal Chemistry. 8 (3): 187–204. doi:10.2174/156802608783498014. PMID 18289088. Archived from the original on 2013-01-12. Retrieved 2018-11-19.
- Lopez-Rodriguez AB, Siopi E, Finn DP, Marchand-Leroux C, Garcia-Segura LM, Jafarian-Tehrani M, Viveros MP (January 2015). "CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice". Cerebral Cortex. 25 (1): 35–45. doi:10.1093/cercor/bht202. PMID 23960212.
- Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, et al. (December 2010). "International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂". Pharmacological Reviews. 62 (4): 588–631. doi:10.1124/pr.110.003004. PMC 2993256. PMID 21079038.
- "PDSP Database - UNC". Archived from the original on 8 November 2013. Retrieved 11 June 2013.
- Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, et al. (January 2010). "Tea catechins' affinity for human cannabinoid receptors". Phytomedicine. 17 (1): 19–22. doi:10.1016/j.phymed.2009.10.001. PMID 19897346.
- Gertsch J, Pertwee RG, Di Marzo V (June 2010). "Phytocannabinoids beyond the Cannabis plant - do they exist?". British Journal of Pharmacology. 160 (3): 523–9. doi:10.1111/j.1476-5381.2010.00745.x. PMC 2931553. PMID 20590562.
- WO patent 200128557, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2001-06-07
- US patent 7241799, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2007-07-10
- Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, et al. (January 2010). "Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity". Journal of Medicinal Chemistry. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781.
- Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, et al. (August 2000). "Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding". Drug and Alcohol Dependence. 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
- "Cannabinoid Receptors: CB2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2012-03-05. Retrieved 2008-11-25.