Opioid receptor:
Opioid receptors are a group of G-protein coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs).
[edit] Major opioid receptor subtypes
There are four major subtypes of opioid receptors:[1]
(I). Name based on order of discovery
The receptors were named using the first letter of the first ligand that was found to bind to them. Morphine was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is `m', but in biochemistry there is a tendency to use Greek letters, thus turning the 'm' to μ. Similarly a drug known as ketocyclazocine was first shown to attach itself to kappa receptors,[3] while the delta receptor was named after the mouse vas deferens tissue in which the receptor was first characterised.[4] An additional opioid receptor was later identified and cloned based on homology with the cDNA. This receptor is known as the nociceptin receptor or ORL 1 receptor.
The opioid receptor types are ~70% identical with differences located at N and C termini. The μ receptor (the μ represents morphine) is perhaps the most important. It is thought that the G protein binds to the third intracellular loop of the opioid receptors. Both in mice and humans the genes for the various receptor subtypes are located on different chromosomes.
Separate subtypes have been identified in human tissue. Research has so far failed to identify the genetic evidence of the subtypes, and it is thought that they arise from post-translational modification of cloned receptor types.[5]
An IUPHAR subcommittee[6][7] has recommended that appropriate terminology for the 3 classical (μ, δ, κ) receptors, and the non-classical (nociceptin) receptor, should be MOP, DOP, KOP and NOP respectively.
[edit] Additional receptors
Sigma receptors (σ) were once considered to be opioid receptors due to the antitussive actions of many opioid drugs being mediated via sigma receptors, and the first selective sigma agonists being derivatives of opioid drugs (e.g. allylnormetazocine), however sigma receptors were found to not be activated by endogenous opioid peptides, and are quite different from the other opioid receptors in both function and gene sequence, so they are now not usually classified with the opioid receptors.
The existence of further opioid receptors has also been suggested, due to pharmacological evidence of actions produced by endogenous opioid peptides but shown not to be mediated through any of the four known opioid receptor subtypes.[8][9][10] The only one of these additional receptors to have been definitively identified is the zeta (ζ) opioid receptor, which has been shown to be a cellular growth factor modulator with met-enkephalin being the endogenous ligand. This receptor is now most commonly referred to as the opioid growth factor receptor (OGFr).[11][12]
Another putative opioid receptor is the epsilon (ε) opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide beta-endorphin was shown to produce additional actions which did not seem to be mediated though any of the known opioid receptors.[13][14] Activation of this receptor produces strong analgesia and release of met-enkephalin, and a number of widely used opioid agonists such as the μ agonist etorphine and the κ agonist bremazocine have been shown to act as agonists for this effect (even in the presence of antagonists to their more well known targets),[15] while buprenorphine has been shown to act as an epsilon antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor,[16][17] however efforts to locate a gene for this receptor have been unsuccessful, and epsilon mediated effects were absent in μ/δ/κ "triple knockout" mice,[18] suggesting the epsilon receptor is likely to be a splice variant or hetero-oligomer derived from alternate post-translational modification of one or more of the known opioid receptors.
[edit] References
- ^ Corbett AD, Henderson G, McKnight AT, Paterson SJ (2006). "75 years of opioid research: the exciting but vain quest for the Holy Grail". Br. J. Pharmacol. 147 Suppl 1: S153–62. doi:10.1038/sj.bjp.0706435. PMID 16402099.
- ^ a b Fine, Perry G.; Russell K. Portenoy (2004). "Chapter 2: The Endogenous Opioid System". A Clinical Guide to Opioid Analgesia, McGraw Hill.
- ^ Anil Aggrawal (1995-05-01). "Opium: the king of narcotics". BLTC Research. Retrieved on 2008-03-21.
- ^ Lord JA, Waterfield AA, Hughes J, Kosterlitz HW. Nature. 1977; 267:495–499.
- ^ Lemke, Thomas L.; Williams, David H.; Foye, William O. (2002). "Opioid Analgesics; Fries, DS". Foye's principles of medicinal chemistry. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-683-30737-1.
- ^ Girdlestone, D (October 2000). "Opioid receptors; Cox BM, Chavkin C, Christie MJ, Civelli O, Evans C, Hamon MD, et al". The IUPHAR Compendium of Receptor Characterization and Classification (2nd Edition ed.). London: IUPHAR Media. pp. pages 321-333.
- ^ "Opioid receptors". IUPHAR Database. International Union of Pharmacology (2008-08-01).
- ^ Grevel J, Yu V, Sadée W. Characterization of a labile naloxone binding site (lambda site) in rat brain. Journal of Neurochemistry. 1985 May;44(5):1647-56. PMID 2985759
- ^ Mizoguchi H, Narita M, Nagase H, Tseng LF. Activation of G-proteins in the mouse pons/medulla by beta-endorphin is mediated by the stimulation of mu- and putative epsilon-receptors. Life Sciences. 2000 Oct 20;67(22):2733-43. PMID 11105989
- ^ Wollemann M, Benyhe S. Non-opioid actions of opioid peptides. Life Sciences. 2004 Jun 4;75(3):257-70. PMID 15135648
- ^ Zagon IS, Verderame MF, Allen SS, McLaughlin PJ. Cloning, sequencing, chromosomal location, and function of cDNAs encoding an opioid growth factor receptor (OGFr) in humans. Brain Research. 2000 Feb 21;856(1-2):75-83. PMID 10677613
- ^ Zagon IS, Verderame MF, McLaughlin PJ. The biology of the opioid growth factor receptor (OGFr). Brain Research. Brain Research Reviews. 2002 Feb;38(3):351-76. PMID 11890982
- ^ Wüster M, Schulz R, Herz A. Specificity of opioids towards the mu-, delta- and epsilon-opiate receptors. Neuroscience Letters. 1979 Dec;15(2-3):193-8. PMID 231238
- ^ Schulz R, Wüster M, Herz A. Pharmacological characterization of the epsilon-opiate receptor. Journal of Pharmacology and Experimental Therapeutics. 1981 Mar;216(3):604-6. PMID 6259326
- ^ Narita M, Tseng LF. Evidence for the existence of the beta-endorphin-sensitive "epsilon-opioid receptor" in the brain: the mechanisms of epsilon-mediated antinociception. Japanese Journal of Pharmacology. 1998 Mar;76(3):233-53. PMID 9593217
- ^ Fujii H, Narita M, Mizoguchi H, Murachi M, Tanaka T, Kawai K, Tseng LF, Nagase H. Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid receptor. Bioorganic and Medicinal Chemistry. 2004 Aug 1;12(15):4133-45. PMID 15246090
- ^ Fujii H, Nagase H. Rational drug design of selective epsilon opioid receptor agonist TAN-821 and antagonist TAN-1014. Current Medicinal Chemistry. 2006;13(10):1109-18. PMID 16719773
- ^ Contet C, Matifas A, Kieffer BL. No evidence for G-protein-coupled epsilon receptor in the brain of triple opioid receptor knockout mouse. European Journal of Pharmacology. 2004 May 25;492(2-3):131-6. PMID 15178356
[edit] See also
[edit] External links
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Transmembrane receptor: G protein-coupled receptors |
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| Class A: Rhodopsin like |
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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, 82, 83, 84, 85, 87, 88, 92, 101, 103, 119, 120, 132, 135, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 172A, 173, 174, 176, 177, 182)
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Adenosine ( A1, A2a, A2b, A3) • P2Y ( 1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
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Other
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Acetylcholine ( M1, M2, M3, M4, M5) • Adrenomedullin • Anaphylatoxin ( C3a, C5a) • Angiotensin ( 1, 2) • Apelin • Bile acid • Bombesin ( BRS3, GRPR, NMBR) • Bradykinin ( B1, B2) • Cannabinoid ( CB1, CB2) • Chemokine • Cholecystokinin ( A, B) • Dopamine ( D1, D2, D3, D4, D5) • EBI2 • Endothelin ( A, B) • Estrogen • Formyl peptide ( 1, L1, L2) • Free fatty acid ( 1, 2, 3, 4) • FSH • Galanin ( 1, 2, 3) • Gonadotropin-releasing hormone ( 1, 2) • Ghrelin • Histamine ( H1, H2, H3, H4) • Kisspeptin • Luteinizing hormone/choriogonadotropin • Lysophospholipid ( 1, 2, 3, 4, 5, 6, 7, 8) • MAS ( 1, 1L, D, E, F, G, X1, X2, X3, X4) • Melanocortin ( 1, 2, 3, 4, 5) • MCHR ( 1, 2) • Melatonin ( 1A, 1B) • Motilin • Opioid ( Delta, Kappa, Mu, Nociceptin, but not Sigma) • Olfactory • Opsin ( 3, 4, 5, 1LW, 1MW, 1SW, RGR, RRH) • Orexin ( 1, 2) • Oxytocin • Oxoglutarate • PAF • Prokineticin ( 1, 2) • Prolactin-releasing peptide • Protease-activated ( 1, 2, 3, 4) • Relaxin ( 1, 2, 3, 4) • Somatostatin ( 1, 2, 3, 4, 5) • SREB • Succinate • TAAR ( 1, 2, 3, 5, 6, 8, 9) • Tachykinin ( 1, 2, 3) • Thyrotropin • Thyrotropin-releasing hormone • Urotensin-II • Vasopressin ( 1A, 1B, 2)
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| Class B: Secretin like |
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GPR ( 56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 157)
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Other
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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) • Parathyroid hormone ( 1, 2) • Secretin • Vasoactive intestinal peptide ( 1, 2)
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Class C: Metabotropic
glutamate / pheromone |
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TAS1R ( 1, 2, 3) • TAS2R ( 1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50)
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Other
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Calcium-sensing receptor • GABA B ( 1, 2) • Glutamate receptor ( Metabotropic glutamate ( 1, 2, 3, 4, 5, 6, 7, 8)) • GPRC6A • GPR ( 156, 158, 179) • RAIG ( 1, 2, 3, 4)
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