Imidazoline receptors are the primary
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s on which
clonidine
Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal ( alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and c ...
and other
imidazolines
Imidazoline is a class of heterocycles formally derived from imidazoles by the reduction of one of the two double bonds. Three isomers are known, 2-imidazolines, 3-imidazolines, and 4-imidazolines. The 2- and 3-imidazolines contain an imine
In ...
act.
There are three main classes of imidazoline receptor: I
1 is involved in inhibition of the
sympathetic nervous system
The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of th ...
to lower blood pressure,
I
2 has as yet uncertain functions but is implicated in several psychiatric conditions,
and I
3 regulates insulin secretion.
Classes
As of 2017, there are three known subtypes of imidazoline receptors: I
1, I
2, and I
3.
I1 receptor
The I
1 receptor appears to be a
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
that is localized on the plasma membrane.
It may be coupled to
PLA2
The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycer ...
signalling and thus prostaglandin synthesis.
In addition, activation inhibits the
sodium-hydrogen antiporter and enzymes of
catecholamine synthesis are induced, suggesting that the I
1 receptor may belong to the
neurocytokine receptor family, since its signaling pathways are similar to those of
interleukin
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
s.
It is found in the neurons of the
reticular formation
The reticular formation is a set of interconnected nuclei that are located throughout the brainstem. It is not anatomically well defined, because it includes neurons located in different parts of the brain. 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
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
or
locus coeruleus
The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system.
The locus coerule ...
.
Animal research suggests that much of the antihypertensive action of
imidazoline
Imidazoline is a class of heterocycles formally derived from imidazoles by the reduction of one of the two double bonds. Three isomers are known, 2-imidazolines, 3-imidazolines, and 4-imidazolines. The 2- and 3-imidazolines contain an imine
In ...
drugs such as
clonidine
Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal ( alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and c ...
is mediated by the I
1 receptor.
In addition, I
1 receptor activation is used in
ophthalmology
Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders.
An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...
to reduce intraocular pressure.
Other putative functions include promoting Na
+ excretion and promoting neural activity during
hypoxia.
I2 receptor
The I
2 receptor binding sites have been defined as being selective binding sites inhibited by the antagonist
idazoxan
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 d ...
that are not blocked by
catecholamines
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a substi ...
.
The major binding site is located on the outer mitochondrial membrane, and is proposed to be an
allosteric site on
monoamine oxidase
Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...
, while another binding site has been found to be brain
creatine kinase
Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phosp ...
.
Other known binding sites have yet to be characterized as of 2017.
Preliminary research in rodents suggests that I
2 receptor agonists may be effective in chronic, but not acute pain, including
fibromyalgia
Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hyp ...
.
I
2 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
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 d ...
, which is non-selective.
I3 receptor
The I
3 receptor regulates
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
secretion from pancreatic
beta cell
Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
s. It may be associated with
ATP-sensitive K+ (K
ATP) 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
Agmatine, also known as 4-aminobutyl-guanidine, is an aminoguanidine that was discovered in 1910 by Albrecht Kossel. Agmatine is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modula ...
(putative
endogenous ligand
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...
at I
1; also interacts with NMDA,
nicotinic
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...
, and α
2 adrenoceptors)
*
Apraclonidine
Apraclonidine ( INN), also known under the brand name Iopidine, is a sympathomimetic used in glaucoma therapy. It is an α2 adrenergic receptor agonist and a weak α1 adrenergic receptor agonist.
Topical apraclonidine is administered at a conc ...
(
α2 adrenoceptor agonist)
* 2-BFI (I
2 agonist,
NMDA antagonist
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...
)
*
Cimetidine
Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.
The development of longer-acting H2 rec ...
(I
1 agonist,
H2 receptor antagonist)
*
Clonidine
Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal ( alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and c ...
(I
1 agonist,
α2 adrenoceptor agonist)
*
LNP-509
*
LNP-911
*
7-Me-marsanidine
*
Dimethyltryptamine
''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...
*
mCPP
*
Moxonidine
*
Oxymetazoline
Oxymetazoline, sold under the brand name Afrin among others, is a topical decongestant and vasoconstrictor medication. It is available over-the-counter as a nasal spray to treat nasal congestion and nosebleeds, as eyedrops to treat eye rednes ...
(I
1 agonist, α
1 adrenoceptor agonist, α
2 partial agonist)
*
Rilmenidine
*
S-23515
*
S-23757
*
Tizanidine
Tizanidine, sold under the brand name Zanaflex among others, is a medication that is used to treat muscle spasticity due to spinal cord injury or multiple sclerosis as well as spastic cerebral palsy. Effectiveness appears similar to baclofen ...
Antagonists
*
BU99006 (alkylating agent, inactivates I
2 receptors)
*
Efaroxan
Efaroxan is an α2-adrenergic receptor antagonist and antagonist of the imidazoline receptor. Synthesis
The Darzens reaction between 2-fluorobenzaldehyde 7848-46-1(1) and Ethyl 2-bromobutyrate 33-68-6(2) gives ethyl 2-ethyl-3-(2-fluorophenyl ...
(I
1, α
2 adrenoceptor antagonist)
*
Idazoxan
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 d ...
(I
1, I
2 antagonist, α
2 adrenoceptor antagonist)
See also
*
imidazoline
Imidazoline is a class of heterocycles formally derived from imidazoles by the reduction of one of the two double bonds. Three isomers are known, 2-imidazolines, 3-imidazolines, and 4-imidazolines. The 2- and 3-imidazolines contain an imine
In ...
*
NISCH
References
External links
*
*
*
{{Imidazolinergics
Receptors