Biology:Cannabinoid receptor 2

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

The cannabinoid receptor 2 (CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene.[1][2] It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids (plant cannabinoids).[1][3] The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).[2]

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.[1] The receptor was identified among cDNAs based on its similarity in amino-acid sequence to the cannabinoid receptor 1 (CB1) receptor, discovered in 1990.[4] The discovery of this receptor helped provide a molecular explanation for the established effects of cannabinoids on the immune system.

Structure

The CB2 receptor is encoded by the CNR2 gene.[1][5] Approximately 360 amino acids comprise the human CB2 receptor, making it somewhat shorter than the 473-amino-acid-long CB1 receptor.[5]

As is commonly seen in G protein-coupled receptors, the CB2 receptor has seven transmembrane spanning domains,[6] a glycosylated N-terminus, and an intracellular C-terminus.[5] 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,[5] perhaps causing the receptor to become less responsive to particular ligands.

The human CB1 and the CB2 receptors possess approximately 44% amino acid similarity.[1] When only the transmembrane regions of the receptors are considered, however, the amino acid similarity between the two receptor subtypes is approximately 68%.[5] 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.[7] 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.[8] In CB2 receptors, lipophilic groups interact with the F5.46 residue, allowing them to form a hydrogen bond with the S3.31 residue.[8] 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.[8]

Mechanism

Like the CB1 receptors, CB2 receptors inhibit the activity of adenylyl cyclase through their Gi/Goα subunits.[9][10] CB2 can also couple to stimulatory Gαs subunits leading to an increase of intracellular cAMP, as has been shown for human leukocytes.[11] Through their Gβγ subunits, CB2 receptors are also known to be coupled to the MAPK-ERK pathway,[9][10][12] a complex and highly conserved signal transduction pathway, which regulates a number of cellular processes in mature and developing tissues.[13] Activation of the MAPK-ERK pathway by CB2 receptor agonists acting through the Gβγ subunit ultimately results in changes in cell migration.[14]

Five recognized cannabinoids are produced endogenously: arachidonoylethanolamine (anandamide), 2-arachidonoyl glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin ether), virodhamine,[9] as well as N-arachidonoyl-dopamine (NADA).[15] 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.[9]

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 whether the CB2 receptor is expressed in the CNS. 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.[16]

Immune system

Initial investigation of CB2 receptor expression patterns focused on the presence of CB2 receptors in the peripheral tissues of the immune system,[6] and found the CB2 receptor mRNA in the spleen, tonsils, and thymus gland.[6] CB2 expression in human peripheral blood mononuclear cells at protein level has been confirmed by whole cell radioligand binding.[11] Northern blot analysis further indicates the expression of the CNR2 gene in immune tissues,[6] where they are primarily responsible for mediating cytokine release.[17] These receptors were localized on immune cells such as monocytes, macrophages, B-cells, and T-cells.[2][6]

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.[18] Unlike the CB1 receptor, in the brain, CB2 receptors are found primarily on microglia.[17][19] The CB2 receptor is expressed in some neurons within the central nervous system (e.g.; the brainstem), but the expression is very low.[20][21] CB2s are expressed on some rat retinal cell types.[22] 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.[23][24]

Gastrointestinal system

CB2 receptors are also found throughout the gastrointestinal system, where they modulate intestinal inflammatory response.[25][26] Thus, CB2 receptor is a potential therapeutic target for inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis.[26][27] 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.[28] Cannabinoid receptor agonists reduce gut motility in IBS patients.[29]

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.[4]

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.[30] 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.[2] 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).[31][32] CB2 also signals via Gαs and increases intracellular cAMP in human leukocytes, leading to induction of interleukins 6 and 10.[11] 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.[30] This reduction causes changes in the expression of critical immunoregulatory genes[31] and ultimately suppression of immune function.[32]

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.[33] 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 hepatocellular carcinoma tumor samples.[34]

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.[2] 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.[35][36] Specifically, the CB2 agonist JWH-015 was shown to induce macrophages to remove native beta-amyloid protein from frozen human tissues.[37] In patients with Alzheimer's disease, beta-amyloid proteins form aggregates known as senile plaques, which disrupt neural functioning.[38]

Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans,[39] 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 [39]

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.[40]

Ligands

Many selective ligands for the CB2 receptor are now available.[41]

Agonists

Partial agonists

Unspecified efficacy agonists

Herbal

Inverse agonists

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 [44]
2-Arachidonoylglycerol 58.3 nM Full agonist 145 nM Full agonist Endogenous [44]
2-Arachidonyl glyceryl ether 21 nM Full agonist 480 nM Full agonist Endogenous
Tetrahydrocannabinol 10 nM Partial agonist 24 nM Partial agonist Phytogenic [45]
EGCG 33.6 μM Agonist >50 μM ? Phytogenic [46]
EGC 35.7 μM Agonist >50 μM ? Phytogenic [46]
ECG 47.3 μM Agonist >50 μM ? Phytogenic [46]
N-alkylamide - - <100 nM Partial agonist Phytogenic [47]
β-Caryophyllene - - <200 nM Full agonist Phytogenic [47]
Falcarinol <1 μM Inverse agonist ? ? Phytogenic [47]
Rutamarin - - <10 μM ? Phytogenic [47]
3,3'-Diindolylmethane - - 1 μM Partial Agonist Phytogenic [47]
AM-1221 52.3 nM Agonist 0.28 nM Agonist Synthetic [48]
AM-1235 1.5 nM Agonist 20.4 nM Agonist Synthetic [49]
AM-2232 0.28 nM Agonist 1.48 nM Agonist Synthetic [49]
UR-144 150 nM Full agonist 1.8 nM Full agonist Synthetic [50]
JWH-007 9.0 nM Agonist 2.94 nM Agonist Synthetic [51]
JWH-015 383 nM Agonist 13.8 nM Agonist Synthetic [51]
JWH-018 9.00 ± 5.00 nM Full agonist 2.94 ± 2.65 nM Full agonist Synthetic [51]

Evolution

Paralogues

Source:[52]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Molecular characterization of a peripheral receptor for cannabinoids". Nature 365 (6441): 61–65. September 1993. doi:10.1038/365061a0. PMID 7689702. Bibcode: 1993Natur.365...61M. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "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): 5720–5732. December 2011. doi:10.4049/jimmunol.1102195. PMID 22048769. 
  3. ↑ "Entrez Gene: CNR2 cannabinoid receptor 2 (macrophage)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1269. 
  4. ↑ 4.0 4.1 "The neurobiology and evolution of cannabinoid signalling". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 356 (1407): 381–408. March 2001. doi:10.1098/rstb.2000.0787. PMID 11316486. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation". Expert Reviews in Molecular Medicine 11: e3. January 2009. doi:10.1017/S1462399409000957. PMID 19152719. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations". European Journal of Biochemistry 232 (1): 54–61. August 1995. doi:10.1111/j.1432-1033.1995.tb20780.x. PMID 7556170. 
  7. ↑ "Cloning and pharmacological characterization of the rat CB(2) cannabinoid receptor". The Journal of Pharmacology and Experimental Therapeutics 292 (3): 886–894. March 2000. PMID 10688601. 
  8. ↑ 8.0 8.1 8.2 "Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis". Journal of Medicinal Chemistry 49 (3): 984–994. February 2006. doi:10.1021/jm050875u. PMID 16451064. 
  9. ↑ 9.0 9.1 9.2 9.3 "Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors". The Journal of Pharmacology and Experimental Therapeutics 315 (2): 828–838. November 2005. doi:10.1124/jpet.105.089474. PMID 16081674. 
  10. ↑ 10.0 10.1 "Cannabinoid signalling". Life Sciences 78 (6): 549–563. January 2006. doi:10.1016/j.lfs.2005.05.055. PMID 16109430. 
  11. ↑ 11.0 11.1 11.2 "Cannabinoid Receptor 2 (CB2) 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. December 2019. doi:10.1021/acsptsci.9b00049. PMID 32259074. 
  12. ↑ "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): 704–711. May 1996. doi:10.1111/j.1432-1033.1996.0704p.x. PMID 8647116. 
  13. ↑ "MAPK signaling in equations and embryos". Fly 3 (1): 62–67. 2009. doi:10.4161/fly.3.1.7776. PMID 19182542. 
  14. ↑ "Regulation of cell motility by mitogen-activated protein kinase". The Journal of Cell Biology 137 (2): 481–492. April 1997. doi:10.1083/jcb.137.2.481. PMID 9128257. 
  15. ↑ "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 Pt 3 (Pt 3): 817–824. November 2000. doi:10.1042/bj3510817. PMID 11042139. 
  16. ↑ "Cannabinoid receptor with an 'identity crisis' gets a second look". Nature Medicine 21 (9): 966–967. September 2015. doi:10.1038/nm0915-966. PMID 26340113. 
  17. ↑ 17.0 17.1 "The pharmacology of cannabinoid receptors and their ligands: an overview". International Journal of Obesity 30 (Suppl 1): S13–S18. April 2006. doi:10.1038/sj.ijo.0803272. PMID 16570099. 
  18. ↑ "Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain". Neuropsychobiology 54 (4): 231–246. 2006. doi:10.1159/000100778. PMID 17356307. 
  19. ↑ "CB2 receptors in the brain: role in central immune function". British Journal of Pharmacology 153 (2): 240–251. January 2008. doi:10.1038/sj.bjp.0707584. PMID 18037916. 
  20. ↑ "Identification and functional characterization of brainstem cannabinoid CB2 receptors". Science 310 (5746): 329–332. October 2005. doi:10.1126/science.1115740. PMID 16224028. Bibcode: 2005Sci...310..329V. https://escholarship.org/uc/item/88q0m818. 
  21. ↑ "Cannabinoid CB2 receptors: immunohistochemical localization in rat brain". Brain Research 1071 (1): 10–23. February 2006. doi:10.1016/j.brainres.2005.11.035. PMID 16472786. 
  22. ↑ "Distribution of CB2 cannabinoid receptor in adult rat retina". Synapse 65 (5): 388–392. May 2011. doi:10.1002/syn.20856. PMID 20803619. 
  23. ↑ "Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats". Addiction Biology 22 (3): 752–765. May 2017. doi:10.1111/adb.12367. PMID 26833913. 
  24. ↑ "Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus". Neuron 90 (4): 795–809. May 2016. doi:10.1016/j.neuron.2016.03.034. PMID 27133464. 
  25. ↑ "Cannabinoids and intestinal motility: welcome to CB2 receptors". British Journal of Pharmacology 142 (8): 1201–1202. August 2004. doi:10.1038/sj.bjp.0705890. PMID 15277313. 
  26. ↑ 26.0 26.1 "Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation". British Journal of Pharmacology 153 (2): 263–270. January 2008. doi:10.1038/sj.bjp.0707486. PMID 17906675. 
  27. ↑ "Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice". British Journal of Pharmacology 154 (5): 1001–1008. July 2008. doi:10.1038/bjp.2008.177. PMID 18469842. 
  28. ↑ "The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome". Neurogastroenterology and Motility 20 (8): 857–868. August 2008. doi:10.1111/j.1365-2982.2008.01175.x. PMID 18710476. 
  29. ↑ "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. November 2011. doi:10.1053/j.gastro.2011.07.036. PMID 21803011. 
  30. ↑ 30.0 30.1 "Inhibition of the cAMP signaling cascade via cannabinoid receptors: a putative mechanism of immune modulation by cannabinoid compounds". Toxicology Letters 102-103: 59–63. December 1998. doi:10.1016/S0378-4274(98)00284-7. PMID 10022233. 
  31. ↑ 31.0 31.1 "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): 1013–1023. April 1998. doi:10.1016/S0006-2952(97)00630-8. PMID 9605425. 
  32. ↑ 32.0 32.1 "Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression". Biochemical Pharmacology 52 (8): 1133–1140. October 1996. doi:10.1016/0006-2952(96)00480-7. PMID 8937419. 
  33. ↑ "Targeting cannabinoid agonists for inflammatory and neuropathic pain". Expert Opinion on Investigational Drugs 16 (7): 951–965. July 2007. doi:10.1517/13543784.16.7.951. PMID 17594182. 
  34. ↑ "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. January 2008. doi:10.1038/sj.bjp.0707442. PMID 17828291. 
  35. ↑ "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): 11136–11141. December 2003. doi:10.1523/JNEUROSCI.23-35-11136.2003. PMID 14657172. 
  36. ↑ "Role of CB2 receptors in neuroprotective effects of cannabinoids". Molecular and Cellular Endocrinology 286 (1-2 Suppl 1): S91–S96. April 2008. doi:10.1016/j.mce.2008.01.001. PMID 18291574. https://hal.archives-ouvertes.fr/hal-00531980/file/PEER_stage2_10.1016%252Fj.mce.2008.01.001.pdf. 
  37. ↑ "The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages". Brain Research 1283 (11): 148–154. August 2009. doi:10.1016/j.brainres.2009.05.098. PMID 19505450. 
  38. ↑ "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology 62 (11): 1984–1989. June 2004. doi:10.1212/01.WNL.0000129697.01779.0A. PMID 15184601. 
  39. ↑ 39.0 39.1 "Is lipid signaling through cannabinoid 2 receptors part of a protective system?". Progress in Lipid Research 50 (2): 193–211. April 2011. doi:10.1016/j.plipres.2011.01.001. PMID 21295074. 
  40. ↑ "Brain cannabinoid CB₂ receptors modulate cocaine's actions in mice". Nature Neuroscience 14 (9): 1160–1166. July 2011. doi:10.1038/nn.2874. PMID 21785434. 
  41. ↑ "Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor". Current Topics in Medicinal Chemistry 8 (3): 187–204. 2008. doi:10.2174/156802608783498014. PMID 18289088. http://www.bentham-direct.org/pages/content.php?CTMC/2008/00000008/00000003/0003R.SGM. Retrieved 2018-11-19. 
  42. ↑ "CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice". Cerebral Cortex 25 (1): 35–45. January 2015. doi:10.1093/cercor/bht202. PMID 23960212. 
  43. ↑ "Interactions of Echinacea spp. Root Extracts and Alkylamides With the Endocannabinoid System and Peripheral Inflammatory Pain". Frontiers in Pharmacology 12: 651292. 2021-04-27. doi:10.3389/fphar.2021.651292. PMID 33986678. 
  44. ↑ 44.0 44.1 "International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂". Pharmacological Reviews 62 (4): 588–631. December 2010. doi:10.1124/pr.110.003004. PMID 21079038. 
  45. ↑ "PDSP Database - UNC". http://pdsp.med.unc.edu/pdsp.php?. 
  46. ↑ 46.0 46.1 46.2 "Tea catechins' affinity for human cannabinoid receptors". Phytomedicine 17 (1): 19–22. January 2010. doi:10.1016/j.phymed.2009.10.001. PMID 19897346. 
  47. ↑ 47.0 47.1 47.2 47.3 47.4 "Phytocannabinoids beyond the Cannabis plant - do they exist?". British Journal of Pharmacology 160 (3): 523–529. June 2010. doi:10.1111/j.1476-5381.2010.00745.x. PMID 20590562. 
  48. ↑ WO patent 200128557, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2001-06-07 
  49. ↑ 49.0 49.1 US patent 7241799, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2007-07-10 
  50. ↑ "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. January 2010. doi:10.1021/jm901214q. PMID 19921781. 
  51. ↑ 51.0 51.1 51.2 "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): 133–140. August 2000. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540. 
  52. ↑ "GeneCards®: The Human Gene Database". https://www.genecards.org/cgi-bin/carddisp.pl?gene=CNR2&keywords=cnr2#paralogs. 

External links

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