View source for Imidazoline receptor

'''Imidazoline receptors''' are the primary [[receptor (biochemistry)|receptor]]s on which [[clonidine]] and other [[2-Imidazoline|imidazolines]] act.<ref name="pmid16529547">{{cite journal | vauthors = Head GA, Mayorov DN | title = Imidazoline receptors, novel agents and therapeutic potential | journal = Cardiovasc Hematol Agents Med Chem | volume = 4 | issue = 1 | pages = 17–32 | date = January 2006 | pmid = 16529547 | url = http://www.bentham-direct.org/pages/content.php?CHAMC/2006/00000004/00000001/003AE.SGM | archive-url = https://archive.today/20130414080524/http://www.bentham-direct.org/pages/content.php?CHAMC/2006/00000004/00000001/003AE.SGM | url-status = usurped | archive-date = April 14, 2013 | doi = 10.2174/187152506775268758 }}</ref><ref name="PMID1327589">{{cite journal | vauthors =  Hamilton CA, Yakubu MA, Howie CA, Reid JL | title = Do Centrally-Acting Antihypertensive Drugs Act at Non-Adrenergic as well as Alpha-2 Adrenoceptor Sites? | journal = Clinical and Experimental Hypertension Part A Theory and Practice | volume = 14 | issue = 5 | pages = 815–835 | date = 1992 | pmid = 1327589 | url = https://www.tandfonline.com/doi/abs/10.3109/10641969209036221 | doi = 10.3109/10641969209036221 }}</ref><ref name="PMID1939285">{{cite journal | vauthors =  Hamilton CA, Yakubu MA, Jardine E, Reid JL | title = Imidazole binding sites in rabbit kidney and forebrain membranes | journal = J Auton Pharmacol | volume = 11 | issue = 5 | pages = 277–83 | date = 1991 | pmid = 1939285 | url = https://onlinelibrary.wiley.com/doi/10.1111/j.1474-8673.1991.tb00325.x | doi = 10.1111/j.1474-8673.1991.tb00325.x }}</ref> There are three main classes of imidazoline receptor: I<sub>1</sub> is involved in inhibition of the [[sympathetic nervous system]] to lower blood pressure,<ref name="Regunathan">{{cite journal|last1=Regunathan|first1=S|last2=Reis|first2=D J|title=Imidazoline Receptors and Their Endogenous Ligands|journal=Annual Review of Pharmacology and Toxicology|date=April 1996|volume=36|issue=1|pages=511–544|doi=10.1146/annurev.pa.36.040196.002455|pmid=8725400}}</ref> I<sub>2</sub> has as yet uncertain functions but is implicated in several psychiatric conditions,<ref name="Kawamura">{{cite journal|last1=Kawamura|first1=Kazunori|last2=Shimoda|first2=Yoko|last3=Kumata|first3=Katsushi|last4=Fujinaga|first4=Masayuki|last5=Yui|first5=Joji|last6=Yamasaki|first6=Tomoteru|last7=Xie|first7=Lin|last8=Hatori|first8=Akiko|last9=Wakizaka|first9=Hidekatsu|last10=Kurihara|first10=Yusuke|last11=Ogawa|first11=Masanao|last12=Nengaki|first12=Nobuki|last13=Zhang|first13=Ming-Rong|title=In vivo evaluation of a new 18F-labeled PET ligand, [18F]FEBU, for the imaging of I2-imidazoline receptors|journal=Nuclear Medicine and Biology|date=April 2015|volume=42|issue=4|pages=406–412|doi=10.1016/j.nucmedbio.2014.12.014|pmid=25583220}}</ref><ref name="Garcia-Sevilla">{{cite journal|last1=GARCIA-SEVILLA|first1=JESUS A.|last2=ESCRIBA|first2=PABLO V.|last3=GUIMON|first3=JOSE|title=Imidazoline Receptors and Human Brain Disorders|journal=Annals of the New York Academy of Sciences|date=June 1999|volume=881|issue=1 IMIDAZOLINE R|pages=392–409|doi=10.1111/j.1749-6632.1999.tb09388.x|pmid=10415944|bibcode=1999NYASA.881..392G|s2cid=10081479}}</ref> and I<sub>3</sub> regulates insulin secretion.<ref name="Head">{{cite journal|last1=Head|first1=G.|last2=Mayorov|first2=D.|title=Imidazoline Receptors, Novel Agents and Therapeutic Potential|journal=Cardiovascular & Hematological Agents in Medicinal Chemistry|date=1 January 2006|volume=4|issue=1|pages=17–32|doi=10.2174/187152506775268758|pmid=16529547}}</ref>

==Classes==
As of 2017, there are three known subtypes of imidazoline receptors: I<sub>1</sub>, I<sub>2</sub>, and I<sub>3</sub>.

===I<sub>1</sub> receptor===
{{Main|NISCH|l1=Nischarin, gene symbol NISCH}}
The I<sub>1</sub> receptor appears to be a [[G protein-coupled receptor]] that is localized on the plasma membrane.<ref name="PMID7677333">{{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}}</ref> It may be coupled to [[Phospholipase A2|PLA2]] signalling and thus prostaglandin synthesis.<ref name="PMID7677333"/><ref name="pmid10415895">{{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 }}</ref> In addition, activation inhibits the [[sodium-hydrogen antiporter]] and enzymes of [[catecholamine synthesis]] are induced, suggesting that the I<sub>1</sub> receptor may belong to the [[neurocytokine receptor]] family, since its signaling pathways are similar to those of [[interleukin]]s.<ref name="pmid10415895"/> It is found in the neurons of the [[reticular formation]], the dorsomedial medulla oblongata, adrenal medulla, renal epithelium, pancreatic islets, platelets, and the prostate.<ref name="PMID7677333"/> They are notably not expressed in the [[cerebral cortex]] or [[locus coeruleus]].<ref name="PMID7677333"/>

Animal research suggests that much of the antihypertensive action of [[imidazoline]] drugs such as [[clonidine]] is mediated by the I<sub>1</sub> receptor.<ref name="PMID7677333"/><ref name = "PMID10921526">{{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}}</ref><ref name="PMID11721890">{{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}}</ref> In addition, I<sub>1</sub> receptor activation is used in [[ophthalmology]] to reduce intraocular pressure.<ref name="PMID7677333"/> Other putative functions include promoting Na<sup>+</sup> excretion and promoting neural activity during [[hypoxia (medical)|hypoxia]].<ref name="PMID7677333"/>

===I<sub>2</sub> receptor===
The I<sub>2</sub> receptor binding sites have been defined as being selective binding sites inhibited by the antagonist [[idazoxan]] that are not blocked by [[catecholamines]].<ref name = "PMID28322973">{{cite journal|last1=Li|first1=JX|title=Imidazoline I<sub>2</sub> 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}}</ref> The major binding site is located on the outer mitochondrial membrane, and is proposed to be an [[allosteric regulation|allosteric]] site on [[monoamine oxidase]], while another binding site has been found to be brain [[creatine kinase]].<ref name = "PMID28322973"/><ref name="PMID7677333"/> Other known binding sites have yet to be characterized {{ as of | 2017 | lc = y }}.<ref name = "PMID28322973"/><ref name="PMID20832472">{{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}}</ref>

Preliminary research in rodents suggests that I<sub>2</sub> receptor agonists may be effective in chronic, but not acute pain, including [[fibromyalgia]].<ref name = "PMID28322973"/> I<sub>2</sub> receptor activation has also been shown to [[Hypothermia|decrease body temperature]], potentially mediating neuroprotective effects seen in rats.<ref name = "PMID28322973"/>

The only known antagonist for the receptor is [[idazoxan]], which is non-selective.<ref name = "PMID28322973"/><ref name="PMID7677333"/>

===I<sub>3</sub> receptor===
The I<sub>3</sub> receptor regulates [[insulin]] secretion from pancreatic [[beta cell]]s. It may be associated with [[ATP-sensitive potassium channel|ATP-sensitive K<sup>+</sup>]] (K<sub>ATP</sub>) channels.<ref name="PMID11472276">{{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}}</ref>

==Ligands==

===I<sub>1</sub> receptors===
====Agonists====
*[[AGN 192403]]<ref name="PMID10781010">{{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}}</ref>
*[[Moxonidine]]{{Inconsistent|date=December 2023|reason=Moxonidine is listed as both a selective I1 receptor agonist and a non-selective agonist.}}

====Antagonists====

===I<sub>2</sub> receptors===
====Agonists====
* [[CR-4056]]
* [[Phenyzoline]] (2-(2-phenylethyl)-4,5-dihydro-1H-imidazole)<ref name = "PMID25308382">{{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...4E6605Q}}</ref>
* [[RS 45041-90]]<ref name = "PMID25308382"/>
* [[Tracizoline]]<ref name = "PMID25308382"/>

====Antagonists====
* [[BU 224]] (disputed)<ref name = "PMID28322973"/>

===I<sub>3</sub> receptors===
No selective ligands are known as of 2017.

===Nonselective ligands===
====Agonists====
* [[Agmatine]] (putative [[endogenous ligand]] at I<sub>1</sub>; also interacts with NMDA, [[nicotinic]], and α<sub>2</sub> adrenoceptors)<ref name="PMID7677333"/>
* [[Apraclonidine]] ([[α2 adrenoceptor|α<sub>2</sub> adrenoceptor]] agonist)
* 2-BFI (I<sub>2</sub> agonist, [[NMDA antagonist]])<ref>{{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}}</ref><ref name = "PMID28322973"/>
* [[Cimetidine]] (I<sub>1</sub> agonist, [[H2 receptor|H<sub>2</sub> receptor]] antagonist)<ref name="PMID7677333"/>
* [[Clonidine]] (I<sub>1</sub> agonist, [[α2 adrenoceptor|α<sub>2</sub> adrenoceptor]] agonist)<ref name="pmid9374795">{{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 }}</ref>
* [[LNP-509]]
* [[LNP-911]]<ref name="Bousquet_2002">{{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 }}</ref>
* [[7-Me-marsanidine]] 
* [[Dimethyltryptamine]]<ref name="Ray p=e9019">{{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 }}</ref>
* [[Meta-Chlorophenylpiperazine|mCPP]]
* [[Moxonidine]]{{Inconsistent|date=December 2023|reason=Moxonidine is listed as both a selective I1 receptor agonist and a non-selective agonist.}}
* [[Oxymetazoline]] (I<sub>1</sub> agonist, α<sub>1</sub> adrenoceptor agonist, α<sub>2</sub> partial agonist)<ref name="PMID7677333" />
* [[Rilmenidine]]
* [[S-23515]]
* [[S-23757]]
* [[Tizanidine]]

====Antagonists====
* [[BU99006]]  (alkylating agent, inactivates I<sub>2</sub> receptors)
* [[Efaroxan]] (I<sub>1</sub>, α<sub>2</sub> adrenoceptor antagonist)
* [[Idazoxan]] (I<sub>1</sub>, I<sub>2</sub> antagonist, α<sub>2</sub> adrenoceptor antagonist)<ref name = "PMID28322973"/><ref name="PMID7677333"/>

==See also==
* [[Imidazoline]]

==References==
{{reflist}}

==External links==
* {{MeshName|Imidazoline+Receptors}}
* {{MeshName|imidazoline receptor 2}}
* {{MeshName|imidazoline I1 receptors}}

{{Antihypertensives and diuretics}}
{{Imidazolinergics}}

[[Category:Receptors]]