Imidazoline receptor explained

Imidazoline receptors are the primary receptors on which clonidine and other imidazolines act.[1] [2] [3] There are three main classes of imidazoline receptor: I1 is involved in inhibition of the sympathetic nervous system to lower blood pressure,[4] I2 has as yet uncertain functions but is implicated in several psychiatric conditions,[5] [6] and I3 regulates insulin secretion.[7]

Classes

As of 2017, there are three known subtypes of imidazoline receptors: I1, I2, and I3.

I1 receptor

The I1 receptor appears to be a G protein-coupled receptor that is localized on the plasma membrane.[8] It may be coupled to PLA2 signalling and thus prostaglandin synthesis.[8] [9] In addition, activation inhibits the sodium-hydrogen antiporter and enzymes of catecholamine synthesis are induced, suggesting that the I1 receptor may belong to the neurocytokine receptor family, since its signaling pathways are similar to those of interleukins.[9] It is found in the neurons of the reticular formation, the dorsomedial medulla oblongata, adrenal medulla, renal epithelium, pancreatic islets, platelets, and the prostate.[8] They are notably not expressed in the cerebral cortex or locus coeruleus.[8]

Animal research suggests that much of the antihypertensive action of imidazoline drugs such as clonidine is mediated by the I1 receptor.[8] [10] [11] In addition, I1 receptor activation is used in ophthalmology to reduce intraocular pressure.[8] Other putative functions include promoting Na+ excretion and promoting neural activity during hypoxia.[8]

I2 receptor

The I2 receptor binding sites have been defined as being selective binding sites inhibited by the antagonist idazoxan that are not blocked by catecholamines.[12] The major binding site is located on the outer mitochondrial membrane, and is proposed to be an allosteric site on monoamine oxidase, while another binding site has been found to be brain creatine kinase.[12] [8] Other known binding sites have yet to be characterized .[12] [13]

Preliminary research in rodents suggests that I2 receptor agonists may be effective in chronic, but not acute pain, including fibromyalgia.[12] I2 receptor activation has also been shown to decrease body temperature, potentially mediating neuroprotective effects seen in rats.[12]

The only known antagonist for the receptor is idazoxan, which is non-selective.[12] [8]

I3 receptor

The I3 receptor regulates insulin secretion from pancreatic beta cells. It may be associated with ATP-sensitive K+ (KATP) channels.[14]

Ligands

I1 receptors

Agonists

Antagonists

I2 receptors

Agonists

Antagonists

I3 receptors

No selective ligands are known as of 2017.

Nonselective ligands

Agonists

Antagonists

See also

Notes and References

  1. Head GA, Mayorov DN . Imidazoline receptors, novel agents and therapeutic potential . Cardiovasc Hematol Agents Med Chem . 4 . 1 . 17–32 . January 2006 . 16529547 . https://archive.today/20130414080524/http://www.bentham-direct.org/pages/content.php?CHAMC/2006/00000004/00000001/003AE.SGM . dead . April 14, 2013 . 10.2174/187152506775268758 .
  2. Hamilton CA, Yakubu MA, Howie CA, Reid JL . Do Centrally-Acting Antihypertensive Drugs Act at Non-Adrenergic as well as Alpha-2 Adrenoceptor Sites? . Clinical and Experimental Hypertension Part A Theory and Practice . 14 . 5 . 815–835 . 1992 . 1327589 . 10.3109/10641969209036221 .
  3. Hamilton CA, Yakubu MA, Jardine E, Reid JL . Imidazole binding sites in rabbit kidney and forebrain membranes . J Auton Pharmacol . 11 . 5 . 277–83 . 1991 . 1939285 . 10.1111/j.1474-8673.1991.tb00325.x .
  4. Regunathan. S. Reis. D J. Imidazoline Receptors and Their Endogenous Ligands. Annual Review of Pharmacology and Toxicology. April 1996. 36. 1. 511–544. 10.1146/annurev.pa.36.040196.002455. 8725400.
  5. Kawamura. Kazunori. Shimoda. Yoko. Kumata. Katsushi. Fujinaga. Masayuki. Yui. Joji. Yamasaki. Tomoteru. Xie. Lin. Hatori. Akiko. Wakizaka. Hidekatsu. Kurihara. Yusuke. Ogawa. Masanao. Nengaki. Nobuki. Zhang. Ming-Rong. In vivo evaluation of a new 18F-labeled PET ligand, [18F]FEBU, for the imaging of I2-imidazoline receptors. Nuclear Medicine and Biology. April 2015. 42. 4. 406–412. 10.1016/j.nucmedbio.2014.12.014. 25583220.
  6. GARCIA-SEVILLA. JESUS A.. ESCRIBA. PABLO V.. GUIMON. JOSE. Imidazoline Receptors and Human Brain Disorders. Annals of the New York Academy of Sciences. June 1999. 881. 1 IMIDAZOLINE R. 392–409. 10.1111/j.1749-6632.1999.tb09388.x. 10415944. 1999NYASA.881..392G. 10081479.
  7. Head. G.. Mayorov. D.. Imidazoline Receptors, Novel Agents and Therapeutic Potential. Cardiovascular & Hematological Agents in Medicinal Chemistry. 1 January 2006. 4. 1. 17–32. 10.2174/187152506775268758. 16529547.
  8. Ernsberger. P. Graves. ME. Graff. LM. Zakieh. N. Nguyen. P. Collins. LA. Westbrooks. KL. Johnson. GG. I1-imidazoline receptors. Definition, characterization, distribution, and transmembrane signaling.. Annals of the New York Academy of Sciences. 12 July 1995. 763. 22–42. 7677333. 10.1111/j.1749-6632.1995.tb32388.x. 85739305.
  9. Ernsberger P . The I1-imidazoline receptor and its cellular signaling pathways . Ann. N. Y. Acad. Sci. . 881 . 1 . 35–53 . June 1999 . 10415895 . 10.1111/j.1749-6632.1999.tb09339.x . 1999NYASA.881...35E . 30065467 . dead . https://web.archive.org/web/20090108161223/http://www.annalsnyas.org/cgi/content/abstract/881/1/35 . 2009-01-08 .
  10. Bousquet. P. Identification and characterization of I1 imidazoline receptors: their role in blood pressure regulation.. American Journal of Hypertension. June 2000. 13. 6 Pt 2. 84S–88S. 10921526. 10.1016/S0895-7061(00)00223-5. free.
  11. Bousquet. P. I1 receptors, cardiovascular function, and metabolism.. American Journal of Hypertension. November 2001. 14. 11 Pt 2. 317S–321S. 11721890. 10.1016/S0895-7061(01)02238-5. free.
  12. Li. JX. Imidazoline I2 receptors: An update.. Pharmacology & Therapeutics. 16 March 2017. 10.1016/j.pharmthera.2017.03.009. 28322973. 178. 5600648. 48–56.
  13. McDonald. GR. Olivieri. A. Ramsay. RR. Holt. A. On the formation and nature of the imidazoline I2 binding site on human monoamine oxidase-B.. Pharmacological Research. December 2010. 62. 6. 475–88. 10.1016/j.phrs.2010.09.001. 20832472.
  14. Morgan. NG. Chan. SL. Imidazoline binding sites in the endocrine pancreas: can they fulfil their potential as targets for the development of new insulin secretagogues?. Current Pharmaceutical Design. September 2001. 7. 14. 1413–31. 11472276. 10.2174/1381612013397366.
  15. Sánchez-Blázquez. P. Boronat. MA. Olmos. G. García-Sevilla. JA. Garzón. J. Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors.. British Journal of Pharmacology. May 2000. 130. 1. 146–52. 10.1038/sj.bjp.0703294. 10781010. 1572044.
  16. Qiu. Y. He. XH. Zhang. Y. Li. JX. Discriminative stimulus effects of the novel imidazoline I₂ receptor ligand CR4056 in rats.. Scientific Reports. 13 October 2014. 4. 6605. 10.1038/srep06605. 25308382. 4194429. 2014NatSR...4E6605Q.
  17. Han. Z. Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.. PLOS ONE. 23741413. 10.1371/journal.pone.0064894. 3669129. 8. 5. 2013. e64894. 2013PLoSO...864894H. etal. free.
  18. Reis DJ, Piletz JE . The imidazoline receptor in control of blood pressure by clonidine and allied drugs. Am. J. Physiol.. 273. 5 Pt 2 . R1569–71. November 1997. 9374795. 10.1152/ajpregu.1997.273.5.R1569.
  19. Bousquet P . I1 imidazoline receptors: From the pharmacological basis to the therapeutic application . Journal für Hypertonie . 6 . 4 . 6–9 . 2002 .
  20. Ray . Thomas S. . Manzoni . Olivier Jacques . Psychedelics and the Human Receptorome . PLOS ONE . 5 . 2 . 2010-02-02 . 1932-6203 . 10.1371/journal.pone.0009019 . 20126400 . e9019. 2814854 . 2010PLoSO...5.9019R . free .

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