Cannabinoid receptor 1

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Cannabinoid receptor 1
Cannabinoid receptor 1
Properties of human protein
Mass / length primary structure 472 amino acids
Secondary to quaternary structure multipass receptor
Isoforms Long, Short, CB1b
Identifier
Gene name CNR1
External IDs
Occurrence
Homology family Cannabinoid receptors
Parent taxon Euteleostomi
Orthologue
human House mouse
Entrez 1268 12801
Ensemble ENSG00000118432 ENSMUSG00000044288
UniProt P21554 P47746
Refseq (mRNA) NM_001160226 NM_007726
Refseq (protein) NP_001153698 NP_031752
Gene locus Chr 6: 88.14 - 88.17 Mb Chr 4: 33.92 - 33.95 Mb
PubMed search 1268 12801

The cannabinoid receptor 1 (or officially short: CNR1 , or alternative abbreviated names: CB1 , CNR , CB-R , CB1A , CANN6 , CB1K5 ) mediates the effects of endogenous cannabinoids as well as exogenously supplied cannabinoids such. B. Δ 9 - Tetrahydrocannabinol from Cannabis sativa in the central nervous system and is therefore part of the endocannabinoid system . It is a transmembrane G protein-coupled receptor that inhibits intracellular adenylyl cyclase activity.

genetics

CNR1 is encoded on chromosome segment 6q14-q15 and is transcribed into a 472 amino acid protein. There are polymorphisms described, with different susceptibility to addiction symptoms after momentary cannabis consumption, severe alcohol dependence or certain forms of schizophrenia may be associated.

Functions

The endogenous cannabinoids such as B. Anandamide influence the migration and networking of nerve cells during brain development.

They are increasingly released in the midbrain during stress and cause an opiate-independent , stress-induced analgesia (pain inhibition ) via the CNR1 .

The following effects are also conveyed through it: hypothermia , reduction of withdrawal symptoms ( addictive behavior ), increased appetite , neuroprotective effects after brain injuries, suppression of unpleasant memories ( reduction of anxiety ), reduction in bone mass.

The chronic administration of Δ 9 -THC reduces the long-term potentiation in the brain and leads to impaired synaptic plasticity in the hippocampus due to a reduced expression of glutamate receptors and a reduction in phosphorylated CREB .

The activity of the cannabinoid receptor 1 in animal experiments on mice and rats by pregnenolone , a prohormone of progesterone blocked. Pregnenolone would thus act as an antagonist .

Ligands

CB 1 - affinity (K i ) CB 1 effect CB 2 affinity (K i ) CB 2 effect Occurrence / origin source
Anandamide 78 nM Full agonist 370 nM Partial agonist endogenous, quadruple unsaturated fatty acid
2-arachidonylglycerol (2-AG) 58.3 or 470 nM Full agonist 145 nM Full agonist endogenous
2-arachidonyl glyceryl ether (2-AGE, noladin ether) 21 nM Full agonist 480 nM Full agonist endogenous -
HU-210 0.41 nM Full agonist - - exogenous , synthetic
AM-1221 52.3 nM Agonist 0.28 nM Agonist exogenous, synthetic
AM-1235 1.5 nM Agonist 20.4 nM Agonist exogenous, synthetic
AM-2232 0.28 nM Agonist 1.48 nM Agonist exogenous, synthetic
AM-2201 1.0 nM Full agonist - - exogenous, synthetic
JWH-007 9.0 nM Agonist 2.94 nM Agonist exogenous, synthetic
JWH-015 383 nM Agonist 13.8 nM Agonist exogenous, synthetic
JWH-018 9.0 ± 5.0 nM Full agonist 2.94 ± 2.65 nM Full agonist exogenous, synthetic
JWH-019 - Agonist - - exogenous, synthetic -
JWH-073 8.9 nM Partial agonist - - exogenous, synthetic
JWH-122 0.69 nM Full agonist - - exogenous, synthetic
CP-47,497 2.1 nM Agonist - - exogenous, synthetic
CP-55,940 2.6 nM Agonist - - exogenous, synthetic
Δ 9 - tetrahydrocannabinol 10 nM Partial agonist 24 nM Partial agonist exogenous, hemp plant (cannabis)
Cannabidiol - Agonist / antagonist - - exogenous, hemp plant
Yangonin 720 nM Agonist - - exogenous, kava plant (Piper methysticum)
(-) - Epigallocatechin-3-O-gallate (EGCG) 33.6 µM Agonist > 50 μM ? exogenous, tea plant (Camellia sinensis)
(-) - Epigallocatechin (EGC) 35.7 µM Agonist - - exogenous, tea plant
(-) - Epicatechin-3-O-gallate (ECG) 47.3 µM Agonist - - exogenous, tea plant
Rimonabant - antagonist - - exogenous, synthetic
Ibipinabant (SLV319, BMS-646,256) - antagonist - -
Otenabant (CP-945,598) - antagonist - -
Pregnenolone - antagonist - - endogenous, prohormone of progesterone
Δ8- tetrahydrocannabivarin - antagonist - -
Cannabigerol - antagonist - -
Virodhamin - antagonist - -
UR-144 150 nM Full agonist 1.8 nM Full agonist exogenous, synthetic
N-arachidonoyl dopamine (NADA) 250 nM Agonist 12 µM ? endogenous

See also

literature

Web links

Individual evidence

  1. ↑ CJ Hopfer, SE Young et al. a .: Cannabis receptor haplotype associated with fewer cannabis dependence symptoms in adolescents. In: American journal of medical genetics. Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics. Volume 141B, Number 8, December 2006, pp. 895-901, doi: 10.1002 / ajmg.b.30378 , PMID 16917946 , PMC 2564870 (free full text).
  2. ↑ LG Schmidt, J. Samochowiec u. a .: Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. In: Drug and alcohol dependence. Volume 65, Number 3, February 2002, pp. 221-224, PMID 11841893 .
  3. ↑ H. Ujike, M. Takaki et al. a .: CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. In: Molecular psychiatry. Volume 7, Number 5, 2002, pp. 515-518, doi: 10.1038 / sj.mp.4001029 , PMID 12082570 .
  4. ↑ Ni Fan: Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Δ9-THC exposure-impaired hippocampal synaptic plasticity . In: J. Neurochem. . 112, No. 3, November 11, 2009, pp. 691-702. doi : 10.1111 / j.1471-4159.2009.06489 . PMID 19912468 .
  5. ↑ Antidote to cannabis high discovered. Der Standard, January 3, 2014, accessed January 5, 2014 .
  6. ↑ M. Vallee, S. Vitiello et al. a .: Pregnenolone Can Protect the Brain from Cannabis Intoxication. In: Science. 343, 2014, pp. 94–98, doi: 10.1126 / science.1243985 .
  7. ↑ a b c C. C. Felder, KE Joyce, EM Briley et al. : Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors . In: Mol Pharmacol . 48, No. 3, September 1995, pp. 443-50. PMID 7565624 .
  8. ↑ a b C. S. Breivogel, G. Griffin, V. Di Marzo, BR Martin: Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. In: Molecular pharmacology. Volume 60, Number 1, July 2001, ISSN  0026-895X , pp. 155-163, PMID 11408610 .
  9. ↑ a b R.G. Pertwee et al. : International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂ . In: Pharmacological Reviews . 62, No. 4, December 2010, pp. 588-631. doi : 10.1124 / pr.110.003004 . PMID 21079038 .
  10. ↑ F. Mauler, J. Mittendorf, E. Horváth, J. De Vry: Characterization of the diarylether sulfonylester (-) - (R) -3- (2-hydroxymethylindanyl-4-oxy) phenyl-4,4,4- trifluoro-1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties. In: Journal of Pharmacology and Experimental Therapeutics . Volume 302, Number 1, July 2002, pp. 359-368, PMID 12065738 .
  11. ↑ a b Patent WO200128557 : Cannabimimetic indole derivatives. Published July 7, 2001 , Inventors: A. Makriyannis, H. Deng. ‌
  12. ↑ a b Patent US7241799 : Cannabimimetic indole derivatives. Published October 10, 2007 , Inventors: A. Makriyannis, H. Deng. ‌
  13. ↑ a b M. M. Aung, G. Griffin, JW Huffman, M. Wu, C. Keel, B. Yang, VM Showalter, ME Abood, BR Martin: Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB (1 ) and CB (2) receptor binding. In: Drug and alcohol dependence. Volume 60, Number 2, August 2000, pp. 133-140, PMID 10940540 .
  14. ↑ MM Aung et al. : Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding . In: Drug and Alcohol Dependence . 60, 2000, pp. 133-140. doi : 10.1016 / s0376-8716 (99) 00152-0 .
  15. ↑ JW Huffman, G. Zengin, MJ Wu, J. Lu, G. Hynd, K. Bushell, AL Thompson, S. Bushell, C. Tartal, DP Hurst, PH Reggio, DE Selley, MP Cassidy, JL Wiley, BR Martin: Structure-activity relationships for 1-alkyl-3- (1-naphthoyl) indoles at the cannabinoid CB (1) and CB (2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB (2) receptor agonists. In: Bioorganic & Medicinal Chemistry . Volume 13, Number 1, January 2005, pp. 89-112, doi: 10.1016 / j.bmc.2004.09.050 , PMID 15582455 .
  16. ↑ Shim JY, Welsh WJ, Howlett AC: "Homology model of the CB1 cannabinoid receptor: sites critical for nonclassical cannabinoid agonist interaction", in: Biopolymers 71, No. 2, 2003, 169-189; PMID 12767117 .
  17. ↑ Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168. Springer. ISBN 3-540-22565-X .
  18. ↑ Little PJ, Compton DR, Johnson MR, Melvin LS, Martin BR: "Pharmacology and stereoselectivity of structurally novel cannabinoids in mice", in: Journal of Pharmacology and Experimental Therapeutics 1988, 247 , 1046-1051.
  19. ↑ PDSP Database - UNC . Archived from the original on November 8, 2013. Info: The archive link was automatically inserted and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved June 11, 2013. @1@ 2Template: Webachiv / IABot / pdsp.med.unc.edu
  20. Jump up ↑ A. Thomas, GL Baillie, AM Phillips, RK Razdan, RA Ross, RG Pertwee: Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. In: British Journal of Pharmacology . Volume 150, number 5, March 2007, pp. 613-623, doi: 10.1038 / sj.bjp.0707133 , PMID 17245363 , PMC 2189767 (free full text).
  21. ↑ A. Ligresti, R. Villano, M. Allarà, I. Ujváry, V. Di Marzo: Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB1 receptor ligand. In: Pharmacological Research . Volume 66, Number 2, August 2012, pp. 163-169, doi: 10.1016 / j.phrs.2012.04.003 , PMID 22525682 .
  22. ↑ a b c G. Korte, A. Dreiseitel, P. Schreier, A. Oehme, S. Locher, S. Geiger, J. Heilmann, PG Sand: Tea catechins' affinity for human cannabinoid receptors. In: Phytomedicine . Volume 17, number 1, January 2010, pp. 19-22, doi: 10.1016 / j.phymed.2009.10.001 , PMID 19897346 .
  23. ↑ JH Lange, HK Coolen u. a .: Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB (1) cannabinoid receptor antagonists. In: Journal of medicinal chemistry. Volume 47, Number 3, January 2004, pp. 627-643, doi: 10.1021 / jm031019q , PMID 14736243 .
  24. ↑ Min-ah Kim, Hoseop Yun, HyunJung Kwak, Jeongmin Kim, Jinhwa Lee: Design, chemical synthesis, and biological evaluation of novel triazolyl analogues of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist. In: Tetrahedron. 64, 2008, pp. 10802-10809, doi: 10.1016 / j.tet.2008.09.057 .
  25. ^ RG Pertwee, A. Thomas, LA Stevenson, RA Ross, SA Varvel, AH Lichtman, BR Martin, RK Razdan: The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo. In: British Journal of Pharmacology. 150, 2007, pp. 586-594, doi: 10.1038 / sj.bjp.0707124 .
  26. ↑ MG Cascio, LA Gauson u. a .: Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. In: British journal of pharmacology. Volume 159, number 1, January 2010, pp. 129-141, doi: 10.1111 / j.1476-5381.2009.00515.x , PMID 20002104 , PMC 2823359 (free full text).
  27. ↑ AC Porter, JM Sauer et al. a .: Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. In: The Journal of pharmacology and experimental therapeutics. Volume 301, Number 3, June 2002, pp. 1020-1024, PMID 12023533 .
  28. ↑ JM Frost, MJ Dart, KR Tietje, TR Garrison, GK Grayson, AV Daza, OF El-Kouhen, BB Yao, GC Hsieh, M. Pai, CZ Zhu, P. Chandran, MD Meyer: Indol-3-ylcycloalkyl ketones : effects of N1 substituted indole side chain variations on CB (2) cannabinoid receptor activity . In: Journal of Medicinal Chemistry . 53, No. 1, January 2010, pp. 295-315. doi : 10.1021 / jm901214q . PMID 19921781 .