Imidazoline receptor#I1 receptor

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

{{Main|NISCH|l1=Nischarin, gene symbol NISCH}}

The I₁ receptor appears to be a G protein-coupled receptor that is localized on the plasma membrane.{{cite journal|last1=Ernsberger|first1=P|last2=Graves|first2=ME|last3=Graff|first3=LM|last4=Zakieh|first4=N|last5=Nguyen|first5=P|last6=Collins|first6=LA|last7=Westbrooks|first7=KL|last8=Johnson|first8=GG|title=I1-imidazoline receptors. Definition, characterization, distribution, and transmembrane signaling.|journal=Annals of the New York Academy of Sciences|date=12 July 1995|volume=763|pages=22–42|pmid=7677333|doi=10.1111/j.1749-6632.1995.tb32388.x|s2cid=85739305}} It may be coupled to PLA2 signalling and thus prostaglandin synthesis.{{cite journal | author = Ernsberger P | title = The I1-imidazoline receptor and its cellular signaling pathways | journal = Ann. N. Y. Acad. Sci. | volume = 881 | issue = 1 | pages = 35–53 | date = June 1999 | pmid = 10415895 | url = http://www.annalsnyas.org/cgi/content/abstract/881/1/35 | doi = 10.1111/j.1749-6632.1999.tb09339.x | bibcode = 1999NYASA.881...35E | s2cid = 30065467 | url-status = dead | archive-url = https://web.archive.org/web/20090108161223/http://www.annalsnyas.org/cgi/content/abstract/881/1/35 | archive-date = 2009-01-08 }} 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. It is found in the neurons of the reticular formation, the dorsomedial medulla oblongata, adrenal medulla, renal epithelium, pancreatic islets, platelets, and the prostate. They are notably not expressed in the cerebral cortex or locus coeruleus.

Animal research suggests that much of the antihypertensive action of imidazoline drugs such as clonidine is mediated by the I₁ receptor.{{cite journal|last1=Bousquet|first1=P|title=Identification and characterization of I1 imidazoline receptors: their role in blood pressure regulation.|journal=American Journal of Hypertension|date=June 2000|volume=13|issue=6 Pt 2|pages=84S–88S|pmid=10921526|doi=10.1016/S0895-7061(00)00223-5|doi-access=free}}{{cite journal|last1=Bousquet|first1=P|title=I1 receptors, cardiovascular function, and metabolism.|journal=American Journal of Hypertension|date=November 2001|volume=14|issue=11 Pt 2|pages=317S–321S|pmid=11721890|doi=10.1016/S0895-7061(01)02238-5|doi-access=free}} In addition, I₁ receptor activation is used in ophthalmology to reduce intraocular pressure. Other putative functions include promoting Na⁺ excretion and promoting neural activity during hypoxia.

The I₂ receptor binding sites have been defined as being selective binding sites inhibited by the antagonist idazoxan that are not blocked by catecholamines.{{cite journal|last1=Li|first1=JX|title=Imidazoline I₂ receptors: An update.|journal=Pharmacology & Therapeutics|date=16 March 2017|doi=10.1016/j.pharmthera.2017.03.009|pmid=28322973|volume=178|pmc=5600648|pages=48–56}} 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. Other known binding sites have yet to be characterized {{ as of | 2017 | lc = y }}.{{cite journal|last1=McDonald|first1=GR|last2=Olivieri|first2=A|last3=Ramsay|first3=RR|last4=Holt|first4=A|title=On the formation and nature of the imidazoline I2 binding site on human monoamine oxidase-B.|journal=Pharmacological Research|date=December 2010|volume=62|issue=6|pages=475–88|doi=10.1016/j.phrs.2010.09.001|pmid=20832472}}

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

The only known antagonist for the receptor is idazoxan, which is non-selective.

The I₃ receptor regulates insulin secretion from pancreatic beta cells. It may be associated with ATP-sensitive K⁺ (K_ATP) channels.{{cite journal|last1=Morgan|first1=NG|last2=Chan|first2=SL|title=Imidazoline binding sites in the endocrine pancreas: can they fulfil their potential as targets for the development of new insulin secretagogues?|journal=Current Pharmaceutical Design|date=September 2001|volume=7|issue=14|pages=1413–31|pmid=11472276|doi=10.2174/1381612013397366}}

• AGN 192403{{cite journal|last1=Sánchez-Blázquez|first1=P|last2=Boronat|first2=MA|last3=Olmos|first3=G|last4=García-Sevilla|first4=JA|last5=Garzón|first5=J|title=Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors.|journal=British Journal of Pharmacology|date=May 2000|volume=130|issue=1|pages=146–52|doi=10.1038/sj.bjp.0703294|pmid=10781010|pmc=1572044}}
• Moxonidine{{Inconsistent|date=December 2023|reason=Moxonidine is listed as both a selective I1 receptor agonist and a non-selective agonist.}}

• CR-4056
• Phenyzoline (2-(2-phenylethyl)-4,5-dihydro-1H-imidazole){{cite journal|last1=Qiu|first1=Y|last2=He|first2=XH|last3=Zhang|first3=Y|last4=Li|first4=JX|title=Discriminative stimulus effects of the novel imidazoline I₂ receptor ligand CR4056 in rats.|journal=Scientific Reports|date=13 October 2014|volume=4|pages=6605|doi=10.1038/srep06605|pmid=25308382|pmc=4194429|bibcode=2014NatSR...4.6605Q}}
• RS 45041-90
• Tracizoline

• BU 224 (disputed)

No selective ligands are known as of 2017.

• Agmatine (putative endogenous ligand at I₁; also interacts with NMDA, nicotinic, and α₂ adrenoceptors)
• Apraclonidine (α₂ adrenoceptor agonist)
• 2-BFI (I₂ agonist, NMDA antagonist){{cite journal|last=Han|first=Z|title=Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.|journal=PLOS ONE| pmid=23741413|doi=10.1371/journal.pone.0064894|pmc=3669129|volume=8|issue=5|year=2013|pages=e64894|bibcode=2013PLoSO...864894H|display-authors=etal|doi-access=free}}
• Cimetidine (I₁ agonist, H₂ receptor antagonist)
• Clonidine (I₁ agonist, α₂ adrenoceptor agonist){{cite journal|vauthors=Reis DJ, Piletz JE|title=The imidazoline receptor in control of blood pressure by clonidine and allied drugs|journal=Am. J. Physiol.|volume=273|issue=5 Pt 2|pages=R1569–71|date=November 1997|pmid=9374795|url=http://ajpregu.physiology.org/content/273/5/R1569.full.pdf|doi=10.1152/ajpregu.1997.273.5.R1569}}{{Dead link|date=September 2024 |bot=InternetArchiveBot |fix-attempted=yes }}
• LNP-509
• LNP-911{{cite journal | author = Bousquet P | title = I1 imidazoline receptors: From the pharmacological basis to the therapeutic application | journal = Journal für Hypertonie | volume = 6 | issue = 4 | pages = 6–9 | year = 2002 | url = http://www.kup.at/kup/pdf/HypSH-4-2002-6.pdf }}
• 7-Me-marsanidine
• Dimethyltryptamine{{cite journal | last=Ray | first=Thomas S. | editor-last=Manzoni | editor-first=Olivier Jacques | title=Psychedelics and the Human Receptorome | journal=PLOS ONE | volume=5 | issue=2 | date=2010-02-02 | issn=1932-6203 | doi=10.1371/journal.pone.0009019 | pmid=20126400 | page=e9019| pmc=2814854 | bibcode=2010PLoSO...5.9019R | doi-access=free }}
• mCPP
• Moxonidine{{Inconsistent|date=December 2023|reason=Moxonidine is listed as both a selective I1 receptor agonist and a non-selective agonist.}}
• Oxymetazoline (I₁ agonist, α₁ adrenoceptor agonist, α₂ partial agonist)
• Rilmenidine
• S-23515
• S-23757
• Tizanidine

• BU99006 (alkylating agent, inactivates I₂ receptors)
• Efaroxan (I₁, α₂ adrenoceptor antagonist)
• Idazoxan (I₁, I₂ antagonist, α₂ adrenoceptor antagonist)

• Imidazoline

{{reflist}}

• {{MeshName|Imidazoline+Receptors}}
• {{MeshName|imidazoline receptor 2}}
• {{MeshName|imidazoline I1 receptors}}

{{Antihypertensives and diuretics}}

{{Imidazolinergics}}

Category:Receptors