Imidazoline receptors are the primary
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
s on which
clonidine
Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic receptor agonist medication used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD), drug withdrawal (e.g., alcohol, opioids, or nic ...
and other
imidazolines
Imidazoline is a heterocycle formally derived from imidazole 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 center, whereas t ...
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 or SANS, sympathetic autonomic nervous system, to differentiate it from the somatic nervous system) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous sy ...
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 ...
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 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 in the brainstem that spans from the lower end of the medulla oblongata to the upper end of the midbrain. The neurons of the reticular formation make up a complex set of neural networks ...
, 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. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
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 in the reticular ...
.
Animal research suggests that much of the antihypertensive action of
imidazoline
Imidazoline is a heterocycle formally derived from imidazole 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 center, whereas t ...
drugs such as
clonidine
Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic receptor agonist medication used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD), drug withdrawal (e.g., alcohol, opioids, or nic ...
is mediated by the I
1 receptor.
In addition, I
1 receptor activation is used in
ophthalmology
Ophthalmology (, ) is the branch of medicine that deals with the diagnosis, treatment, and surgery of eye diseases and disorders.
An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a ...
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 di ...
that are not blocked by
catecholamines
A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, 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.
...
.
The major binding site is located on the outer mitochondrial membrane, and is proposed to be an
allosteric
In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...
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 fi ...
, 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 phos ...
.
Other known binding sites have yet to be characterized .
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 functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...
.
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 di ...
, 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 insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
secretion from pancreatic
beta cell
Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vi ...
s. It may be associated with
ATP-sensitive K+ (K
ATP) channels.
Ligands
I1 receptors
Agonists
*
AGN 192403
AGN may refer to:
* Active galactic nucleus
* Acute glomerulonephritis
* Agutaynen language
* Allergan
Allergan plc is an American, Irish-domiciled pharmaceutical company that acquires, develops, manufactures and markets brand name drugs and me ...
*
Moxonidine
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 ...
Antagonists
I2 receptors
Agonists
*
CR-4056
CR-4056 is an analgesic drug candidate with a novel mechanism of action, acting as a ligand for the imidazoline receptor I2. It showed promising results in animal studies against various types of neuropathic pain, and has reached Phase II human ...
*
Phenyzoline (2-(2-phenylethyl)-4,5-dihydro-1H-imidazole)
*
RS 45041-90
RS may refer to:
Businesses and organizations
* RS Group, entertainment & media company in Thailand
* RS Group plc, British electronics & industrial distributor in England with brands including RS Components and RS Americas, Inc
* RS Infotainme ...
*
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, 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 molecu ...
(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 Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a ...
at I
1; also interacts with NMDA,
nicotinic, 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 humans and animals; the state of anesthesia they ind ...
)
*
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.
With the development of proton pump ...
(I
1 agonist,
H2 receptor antagonist)
*
Clonidine
Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic receptor agonist medication used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD), drug withdrawal (e.g., alcohol, opioids, or nic ...
(I
1 agonist,
α2 adrenoceptor agonist)
*
LNP-509
*
LNP-911
*
7-Me-marsanidine
*
Dimethyltryptamine
Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a Psychedelic drug, serotonergic hallucinogen and Investigational New Drug, investigational drug of the substituted tryptamine, tryptamine family tha ...
*
mCPP
*
Moxonidine
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 ...
*
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 eye drops 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 an alpha-2 (α2) adrenergic receptor agonist, similar to clonidine, that is used to treat muscle spasticity due to spinal cord injury, multiple sclerosis, and spastic cerebral ...
Antagonists
*
BU99006 (alkylating agent, inactivates I
2 receptors)
*
Efaroxan
Efaroxan is an alpha-2 adrenergic receptor, α2-adrenergic receptor receptor antagonist, antagonist and receptor antagonist, antagonist of the imidazoline receptor. Synthesis
The Darzens reaction between 2-fluorobenzaldehyde 7848-46-1(1) and ...
(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 di ...
(I
1, I
2 antagonist, α
2 adrenoceptor antagonist)
See also
*
Imidazoline
Imidazoline is a heterocycle formally derived from imidazole 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 center, whereas t ...
References
External links
*
*
*
{{Imidazolinergics
Receptors