Imidazoline receptors are the primary receptors on which clonidine and other imidazolines act. There are three main classes of imidazoline receptor: I1 is involved in inhibition of the sympathetic nervous system to lower blood pressure, I2 has as yet uncertain functions but is implicated in several psychiatric conditions, and I3 regulates insulin secretion.
As of 2017, there are three known subtypes of imidazoline receptors: I1, I2, and I3.
The I1 receptor appears to be a G protein-coupled receptor that is localized on the plasma membrane. It may be coupled to PLA2 signalling and thus prostaglandin synthesis. 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. 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. 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.
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.
- Phenyzoline (2-(2-phenylethyl)-4,5-dihydro-1H-imidazole)
- RS 45041-90
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)
- Cimetidine (I1 agonist, H2 receptor antagonist)
- Clonidine (I1 agonist, α2 adrenoceptor agonist)
- Oxymetazoline (I1 agonist, α1 adrenoceptor agonist, α2 partial agonist)
- Head GA, Mayorov DN (January 2006). "Imidazoline receptors, novel agents and therapeutic potential". Cardiovasc Hematol Agents Med Chem. 4 (1): 17–32. doi:10.2174/187152506775268758. PMID 16529547.
- Regunathan, S; Reis, D J (April 1996). "Imidazoline Receptors and Their Endogenous Ligands". Annual Review of Pharmacology and Toxicology. 36 (1): 511–544. doi:10.1146/annurev.pa.36.040196.002455. PMID 8725400.
- 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 (April 2015). "In vivo evaluation of a new 18F-labeled PET ligand, [18F]FEBU, for the imaging of I2-imidazoline receptors". Nuclear Medicine and Biology. 42 (4): 406–412. doi:10.1016/j.nucmedbio.2014.12.014. PMID 25583220.
- GARCIA-SEVILLA, JESUS A.; ESCRIBA, PABLO V.; GUIMON, JOSE (June 1999). "Imidazoline Receptors and Human Brain Disordersa". Annals of the New York Academy of Sciences. 881 (1 IMIDAZOLINE R): 392–409. Bibcode:1999NYASA.881..392G. doi:10.1111/j.1749-6632.1999.tb09388.x. PMID 10415944. S2CID 10081479.
- Head, G.; Mayorov, D. (1 January 2006). "Imidazoline Receptors, Novel Agents and Therapeutic Potential". Cardiovascular & Hematological Agents in Medicinal Chemistry. 4 (1): 17–32. doi:10.2174/187152506775268758. PMID 16529547.
- Ernsberger, P; Graves, ME; Graff, LM; Zakieh, N; Nguyen, P; Collins, LA; Westbrooks, KL; Johnson, GG (12 July 1995). "I1-imidazoline receptors. Definition, characterization, distribution, and transmembrane signaling". Annals of the New York Academy of Sciences. 763: 22–42. doi:10.1111/j.1749-6632.1995.tb32388.x. PMID 7677333. S2CID 85739305.
- Ernsberger P (June 1999). "The I1-imidazoline receptor and its cellular signaling pathways". Ann. N. Y. Acad. Sci. 881 (1): 35–53. Bibcode:1999NYASA.881...35E. doi:10.1111/j.1749-6632.1999.tb09339.x. PMID 10415895. S2CID 30065467. Archived from the original on 2009-01-08.
- Bousquet, P (June 2000). "Identification and characterization of I1 imidazoline receptors: their role in blood pressure regulation". American Journal of Hypertension. 13 (6 Pt 2): 84S–88S. doi:10.1016/S0895-7061(00)00223-5. PMID 10921526.
- Bousquet, P (November 2001). "I1 receptors, cardiovascular function, and metabolism". American Journal of Hypertension. 14 (11 Pt 2): 317S–321S. doi:10.1016/S0895-7061(01)02238-5. PMID 11721890.
- Li, JX (16 March 2017). "Imidazoline I2 receptors: An update". Pharmacology & Therapeutics. 178: 48–56. doi:10.1016/j.pharmthera.2017.03.009. PMC 5600648. PMID 28322973.
- McDonald, GR; Olivieri, A; Ramsay, RR; Holt, A (December 2010). "On the formation and nature of the imidazoline I2 binding site on human monoamine oxidase-B". Pharmacological Research. 62 (6): 475–88. doi:10.1016/j.phrs.2010.09.001. PMID 20832472.
- Morgan, NG; Chan, SL (September 2001). "Imidazoline binding sites in the endocrine pancreas: can they fulfil their potential as targets for the development of new insulin secretagogues?". Current Pharmaceutical Design. 7 (14): 1413–31. doi:10.2174/1381612013397366. PMID 11472276.
- Sánchez-Blázquez, P; Boronat, MA; Olmos, G; García-Sevilla, JA; Garzón, J (May 2000). "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. 130 (1): 146–52. doi:10.1038/sj.bjp.0703294. PMC 1572044. PMID 10781010.
- Qiu, Y; He, XH; Zhang, Y; Li, JX (13 October 2014). "Discriminative stimulus effects of the novel imidazoline I₂ receptor ligand CR4056 in rats". Scientific Reports. 4: 6605. Bibcode:2014NatSR...4E6605Q. doi:10.1038/srep06605. PMC 4194429. PMID 25308382.
- Han, Z; et al. (2013). "Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection". PLOS ONE. 8 (5): e64894. Bibcode:2013PLoSO...864894H. doi:10.1371/journal.pone.0064894. PMC 3669129. PMID 23741413.
- Reis DJ, Piletz JE (November 1997). "The imidazoline receptor in control of blood pressure by clonidine and allied drugs" (PDF). Am. J. Physiol. 273 (5 Pt 2): R1569–71. doi:10.1152/ajpregu.1997.273.5.R1569. PMID 9374795.
- Bousquet P (2002). "I1 imidazoline receptors: From the pharmacological basis to the therapeutic application" (PDF). Journal für Hypertonie. 6 (4): 6–9.
- Ray, Thomas S. (2010-02-02). Manzoni, Olivier Jacques (ed.). "Psychedelics and the Human Receptorome". PLOS ONE. 5 (2): e9019. Bibcode:2010PLoSO...5.9019R. doi:10.1371/journal.pone.0009019. ISSN 1932-6203. PMC 2814854. PMID 20126400.