Imidazoline receptor

Classes

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

I₁ receptor

Main article: NISCH

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.

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. 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 .

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.

I₃ receptor

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

Ligands

I₁ receptors

Agonists

• AGN 192403
• Moxonidine

Antagonists

I₂ receptors

Agonists

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

Antagonists

• BU 224 (disputed)

I₃ receptors

No selective ligands are known as of 2017.

Nonselective ligands

Agonists

• 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)
• LNP-509
• LNP-911
• 7-Me-marsanidine
• Dimethyltryptamine
• mCPP
• Moxonidine
• Oxymetazoline (I1 agonist, α1 adrenoceptor agonist, α2 partial agonist)
• Rilmenidine
• S-23515
• S-23757
• Tizanidine

Antagonists

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

References

References

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11. (November 2001). "I1 receptors, cardiovascular function, and metabolism.". American Journal of Hypertension.
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