Imidazoline receptor

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]

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.^[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]

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 as of 2017^[update].^[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]

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

• AGN 192403^[15]
• Moxonidine^{[inconsistent]}

• CR-4056
• Phenyzoline (2-(2-phenylethyl)-4,5-dihydro-1H-imidazole)^[16]
• RS 45041-90^[16]
• Tracizoline^[16]

• BU 224 (disputed)^[12]

No selective ligands are known as of 2017.

• Agmatine (putative endogenous ligand at I₁; also interacts with NMDA, nicotinic, and α₂ adrenoceptors)^[8]
• Apraclonidine (α₂ adrenoceptor agonist)
• 2-BFI (I₂ agonist, NMDA antagonist)^[17][12]
• Cimetidine (I₁ agonist, H₂ receptor antagonist)^[8]
• Clonidine (I₁ agonist, α₂ adrenoceptor agonist)^[18]
• LNP-509
• LNP-911^[19]
• 7-Me-marsanidine
• Dimethyltryptamine^[20]
• mCPP
• Moxonidine^{[inconsistent]}
• Oxymetazoline (I₁ agonist, α₁ adrenoceptor agonist, α₂ partial agonist)^[8]
• Rilmenidine
• S-23515
• S-23757
• Tizanidine

• BU99006 (alkylating agent, inactivates I₂ receptors)
• Efaroxan (I₁, α₂ adrenoceptor antagonist)
• Idazoxan (I₁, I₂ antagonist, α₂ adrenoceptor antagonist)^[12][8]

• Imidazoline

• Imidazoline+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• imidazoline receptor 2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• imidazoline I1 receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)