Imidazoline receptor

Last updated

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]

Contents

Classes

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

I1 receptor

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]

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. [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. [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]

I3 receptor

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

Ligands

I1 receptors

Agonists

Antagonists

I2 receptors

Agonists

Antagonists

I3 receptors

No selective ligands are known as of 2017.

Nonselective ligands

Agonists

Antagonists

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

See also

Related Research Articles

<span class="mw-page-title-main">Adrenergic receptor</span> Class of G protein-coupled receptors

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">Agonist</span> Chemical which binds to and activates a biochemical receptor

An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

<span class="mw-page-title-main">Clonidine</span> Pharmaceutical drug

Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic receptor agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. The drug is often prescribed off-label for tics. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.

<span class="mw-page-title-main">Receptor antagonist</span> Type of receptor ligand or drug that blocks a biological response

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of receptor proteins. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.

Agmatine, also known as 4-aminobutyl-guanidine, was discovered in 1910 by Albrecht Kossel. It is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, ion channels, nitric oxide (NO) synthesis, and polyamine metabolism and this provides bases for further research into potential applications.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

<span class="mw-page-title-main">Moxonidine</span> Antihypertensive medication

Moxonidine (INN) is a new-generation alpha-2/imidazoline receptor agonist antihypertensive drug licensed for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors, and calcium channel blockers are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the insulin resistance syndrome, apparently independent of blood pressure reduction. It is also a growth hormone releaser. It is manufactured by Solvay Pharmaceuticals under the brand name Physiotens and Moxon.

<span class="mw-page-title-main">2-Imidazoline</span> Chemical compound

2-Imidazoline (Preferred IUPAC name: 4,5-dihydro-1H-imidazole) is one of three isomers of the nitrogen-containing heterocycle imidazoline, with the formula C3H6N2. The 2-imidazolines are the most common imidazolines commercially, as the ring exists in some natural products and some pharmaceuticals. They also have been examined in the context of organic synthesis, coordination chemistry, and homogeneous catalysis.

<span class="mw-page-title-main">Alpha-2 adrenergic receptor</span> Protein family

The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

<span class="mw-page-title-main">Alpha-adrenergic agonist</span> Class of drugs

Alpha-adrenergic agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2. Alpha 2 receptors are associated with sympatholytic properties. Alpha-adrenergic agonists have the opposite function of alpha blockers. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity. The activation of α1 stimulates the membrane bound enzyme phospholipase C, and activation of α2 inhibits the enzyme adenylate cyclase. Inactivation of adenylate cyclase in turn leads to the inactivation of the secondary messenger cyclic adenosine monophosphate and induces smooth muscle and blood vessel constriction.

<span class="mw-page-title-main">Cirazoline</span> Chemical compound

Cirazoline is a full agonist at the α1A adrenergic receptor, a partial agonist at both the α1B and α1D adrenergic receptors, and a nonselective antagonist to the α2 adrenergic receptor. It is believed that this combination of properties could make cirazoline an effective vasoconstricting agent.

<span class="mw-page-title-main">Adrenergic antagonist</span> Type of drug

An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.

<span class="mw-page-title-main">Alpha-2A adrenergic receptor</span> Protein-coding gene in the species Homo sapiens

The alpha-2A adrenergic receptor, also known as ADRA2A, is an α2 adrenergic receptor, and also denotes the human gene encoding it.

<span class="mw-page-title-main">Idazoxan</span> Chemical compound

Idazoxan (INN) is a drug which is used in scientific research. It acts as both a selective α2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. Idazoxan has been under investigation as an antidepressant, but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in schizophrenia. Due to its α2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics, possibly by enhancing dopamine neurotransmission in the prefrontal cortex of the brain, a brain area thought to be involved in the pathogenesis of schizophrenia.

<span class="mw-page-title-main">Alazocine</span> Synthetic opioid analgesic

Alazocine, also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and opioid antagonist. Moreover, one of its enantiomers was the first compound that was found to selectively label the σ1 receptor, and led to the discovery and characterization of the receptor.

<span class="mw-page-title-main">Corynanthine</span> Chemical compound

Corynanthine, also known as rauhimbine, is an alkaloid found in the Rauvolfia and Corynanthe genera of plants. It is one of the two diastereoisomers of yohimbine, the other being rauwolscine. It is also related to ajmalicine.

<span class="mw-page-title-main">Fluparoxan</span> Chemical compound

Fluparoxan is a potent α2-adrenergic receptor antagonist with excellent selectivity for this receptor over the α1-adrenergic receptor (2,630-fold), and is the only well-studied α2-adrenergic receptor antagonist in its structural family which does not antagonize any variant of the imidazoline receptor. It was shown to possess central α2-adrenoceptor antagonist activity after oral doses in man and was patented as an antidepressant by Glaxo in the early 1980s, but its development was discontinued when the compound failed to show a clear clinical advantage over existing therapies.

<span class="mw-page-title-main">Tiamenidine</span> Chemical compound

Tiamenidine (BAN, USAN, INN, also known as thiamenidine, Hoe 440) is an imidazoline compound that shares many of the pharmacological properties of clonidine. It is a centrally-acting α2 adrenergic receptor agonist (IC50 = 9.1 nM). It also acts as an α1-adrenergic receptor agonist to a far lesser extent (IC50 = 4.85 μM). In hypertensive volunteers, like clonidine, it significantly increased sinus node recovery time and lowered cardiac output. It was marketed (as tiamenidine hydrochloride) by Sanofi-Aventis under the brand name Sundralen for the management of essential hypertension.

<span class="mw-page-title-main">Aganodine</span> Chemical compound

Aganodine is a guanidine that activates presynaptic imidazoline receptors. Through its agonism at imidazoline receptors, aganodine inhibits the presynaptic release of norepinephrine.

References

  1. ↑ 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. Archived from the original on April 14, 2013.{{cite journal}}: CS1 maint: unfit URL (link)
  2. ↑ Hamilton CA, Yakubu MA, Howie CA, Reid JL (1992). "Do Centrally-Acting Antihypertensive Drugs Act at Non-Adrenergic as well as Alpha-2 Adrenoceptor Sites?". Clinical and Experimental Hypertension Part A Theory and Practice. 14 (5): 815–835. doi:10.3109/10641969209036221. PMID   1327589.
  3. ↑ Hamilton CA, Yakubu MA, Jardine E, Reid JL (1991). "Imidazole binding sites in rabbit kidney and forebrain membranes". J Auton Pharmacol. 11 (5): 277–83. doi:10.1111/j.1474-8673.1991.tb00325.x. PMID   1939285.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ GARCIA-SEVILLA, JESUS A.; ESCRIBA, PABLO V.; GUIMON, JOSE (June 1999). "Imidazoline Receptors and Human Brain Disorders". 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.
  7. ↑ 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.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 13 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.
  9. 1 2 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.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 3 4 5 6 7 8 9 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. 1 2 3 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.
  17. ↑ 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.
  18. ↑ 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.[ permanent dead link ]
  19. ↑ Bousquet P (2002). "I1 imidazoline receptors: From the pharmacological basis to the therapeutic application" (PDF). Journal für Hypertonie. 6 (4): 6–9.
  20. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.