Alpha-2 adrenergic receptor

The α_2A adrenergic receptor is localised in the following central nervous system (CNS) structures:{{cite journal | vauthors = Saunders C, Limbird LE | title = Localization and trafficking of alpha2-adrenergic receptor subtypes in cells and tissues | journal = Pharmacology & Therapeutics | volume = 84 | issue = 2 | pages = 193–205 | date = November 1999 | pmid = 10596906 | doi = 10.1016/S0163-7258(99)00032-7 }}

• Brainstem (especially the locus coeruleus as presynaptic & somatodendritic autoreceptor {{cite journal | vauthors = Saunders C, Limbird LE | title = Localization and trafficking of alpha2-adrenergic receptor subtypes in cells and tissues | journal = Pharmacology & Therapeutics | volume = 84 | issue = 2 | pages = 193–205 | date = November 1999 | pmid = 10596906 | doi = 10.1016/S0163-7258(99)00032-7 }})
• Midbrain
• Hypothalamus
• Olfactory system
• Hippocampus
• Spinal cord
• Cerebral cortex
• Cerebellum
• Septum

Whereas the α_2B adrenergic receptor is localised in the following CNS structures:

• Thalamus
• Pyramidal layer of the hippocampus
• Cerebellar Purkinje layer

and the α_2C adrenergic receptor is localised in the CNS structures:

• Midbrain
• Thalamus
• Amygdala
• Dorsal root ganglia
• Olfactory system
• Hippocampus
• Cerebral cortex
• Basal ganglia
• Substantia nigra
• Ventral tegmentum

The α₂-adrenergic receptor is classically located on vascular prejunctional terminals where it inhibits the release of norepinephrine (noradrenaline) in a form of negative feedback.{{cite book | title = Introduction to Cardiovascular Physiology | edition = 3rd | publisher = Arnold Publishers | vauthors = Levick JR | chapter = Chapter 14.1: Sympathetic vasoconstrictor nerves | date = 2000 }} It is also located on the vascular smooth muscle cells of certain blood vessels, such as those found in skin arterioles or on veins, where it sits alongside the more plentiful α₁-adrenergic receptor. The α₂-adrenergic receptor binds both norepinephrine released by sympathetic postganglionic fibers and epinephrine (adrenaline) released by the adrenal medulla, binding norepinephrine with slightly higher affinity.{{cite book| vauthors = Boron WF |title=Medical Physiology: A Cellular and Molecular Approach|year=2012|page=360}} It has several general functions in common with the α₁-adrenergic receptor, but also has specific effects of its own. Agonists (activators) of the α₂-adrenergic receptor are frequently used in anaesthesia where they affect sedation, muscle relaxation and analgesia through effects on the central nervous system (CNS).{{cite journal | vauthors = Khan ZP, Ferguson CN, Jones RM | title = alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role | journal = Anaesthesia | volume = 54 | issue = 2 | pages = 146–165 | date = February 1999 | pmid = 10215710 | doi = 10.1046/j.1365-2044.1999.00659.x | doi-access = free }}

In the brain, α₂-adrenergic receptors can be localized either pre- or post-synaptically, and the majority of receptors appear to be post-synaptic.{{cite journal | vauthors = U'Prichard DC, Bechtel WD, Rouot BM, Snyder SH | title = Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine | journal = Molecular Pharmacology | volume = 16 | issue = 1 | pages = 47–60 | date = July 1979 | pmid = 39248 | doi = | url = }} For example, the α_2A adrenergic receptor subtype is post-synaptic in the prefrontal cortex and these receptors strengthen cognitive and executive functions by inhibiting cAMP opening of potassium channels, thus enhancing prefrontal connections and neuronal firing.{{cite journal | vauthors = Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF | title = Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex | journal = Cell | volume = 129 | issue = 2 | pages = 397–410 | date = April 2007 | pmid = 17448997 | doi = 10.1016/j.cell.2007.03.015 }} The α_2A-adrenergic agonist, guanfacine, is now used to treat prefrontal cortical cognitive disorders such as attention deficit hyperactivity disorder (ADHD).{{cite journal | vauthors = Arnsten AF | title = Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species | journal = Neurobiology of Learning and Memory | volume = 176 | issue = | pages = 107327 | date = December 2020 | pmid = 33075480 | doi = 10.1016/j.nlm.2020.107327 | pmc = 7567669 }}

Common effects include:

• Suppression of release of norepinephrine (noradrenaline) by negative feedback
• Transient hypertension (increase in blood pressure), followed by a sustained hypotension (decrease in blood pressure)
• Vasoconstriction of certain arteries{{cite book | vauthors = Hardman JG, Limbird LE, Gilman AG |title=Goodman & Gilman's the pharmacological basis of therapeutics |date=2001 |publisher=McGraw-Hill |location=New York |isbn=978-0-07-135469-1 |edition=10th | page = 140 }}
• Vasoconstriction of arteries to heart (coronary artery);{{cite journal | vauthors = Woodman OL, Vatner SF | title = Coronary vasoconstriction mediated by alpha 1- and alpha 2-adrenoceptors in conscious dogs | journal = The American Journal of Physiology | volume = 253 | issue = 2 Pt 2 | pages = H388-H393 | date = August 1987 | pmid = 2887122 | doi = 10.1152/ajpheart.1987.253.2.H388 }} however, the extent of this effect may be limited and may be negated by the vasodilatory effect from β₂ receptors{{cite journal | vauthors = Sun D, Huang A, Mital S, Kichuk MR, Marboe CC, Addonizio LJ, Michler RE, Koller A, Hintze TH, Kaley G | title = Norepinephrine elicits beta2-receptor-mediated dilation of isolated human coronary arterioles | journal = Circulation | volume = 106 | issue = 5 | pages = 550–555 | date = July 2002 | pmid = 12147535 | doi = 10.1161/01.CIR.0000023896.70583.9F | doi-access = free }}
• Constriction of some vascular smooth muscle{{cite book | title = Basic & Clinical Pharmacology | edition = 11th | publisher = McGraw Hill | vauthors = Katzung B, Masters S, Trevor A | chapter = Chapter 9. Adrenoceptor Agonists & Sympathomimetic Drugs | isbn = 978-0-07-160405-5 }}
• Venoconstriction of veins{{cite journal | vauthors = Elliott J | title = Alpha-adrenoceptors in equine digital veins: evidence for the presence of both alpha1 and alpha2-receptors mediating vasoconstriction | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 20 | issue = 4 | pages = 308–317 | date = August 1997 | pmid = 9280371 | doi = 10.1046/j.1365-2885.1997.00078.x }}
• Decrease motility of smooth muscle in gastrointestinal tract{{cite journal | vauthors = Sagrada A, Fargeas MJ, Bueno L | title = Involvement of alpha-1 and alpha-2 adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat | journal = Gut | volume = 28 | issue = 8 | pages = 955–959 | date = August 1987 | pmid = 2889649 | pmc = 1433140 | doi = 10.1136/gut.28.8.955 }}
• Inhibition of lipolysis
• Facilitation of the cognitive functions associated with the prefrontal cortex (PFC; working memory, attention, executive functioning, etc.){{cite web|title=Alpha-2 Agonists in the Treatment of ADHD| vauthors = Arnsten AF |work=Medscape Psychiatry|publisher=WebMD|date=26 July 2007|access-date=13 November 2013|url=http://www.medscape.org/viewarticle/560074}}
• Sedation
• Analgesia

Individual actions of the α₂ receptor include:

• Mediates synaptic transmission in pre- and postsynaptic nerve terminals
• Decrease release of acetylcholine
• Decrease release of norepinephrine
• Inhibit norepinephrine system in brain
• Inhibition{{cite journal | vauthors = Wright EE, Simpson ER | title = Inhibition of the lipolytic action of beta-adrenergic agonists in human adipocytes by alpha-adrenergic agonists | journal = Journal of Lipid Research | volume = 22 | issue = 8 | pages = 1265–1270 | date = November 1981 | pmid = 6119348 | doi = 10.1016/S0022-2275(20)37319-3 | doi-access = free }} of lipolysis in adipose tissue
• Inhibition of insulin release in pancreas{{cite book | vauthors = Fitzpatrick D, Purves D, Augustine G | title = Neuroscience | publisher = Sinauer | location = Sunderland, Mass | year = 2004 | edition = Third | chapter = Table 20:2 | isbn = 978-0-87893-725-7 }}
• Induction of glucagon release from pancreas
• platelet aggregation
• Contraction of sphincters of the gastrointestinal tract
• Decreased secretion from salivary gland
• Relax gastrointestinal tract (presynaptic effect)
• Decreased aqueous humor fluid production from the ciliary body

The α subunit of an inhibitory G protein - G_i dissociates from the G protein,{{cite journal | vauthors = Qin K, Sethi PR, Lambert NA | title = Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins | journal = FASEB Journal | volume = 22 | issue = 8 | pages = 2920–2927 | date = August 2008 | pmid = 18434433 | pmc = 2493464 | doi = 10.1096/fj.08-105775 | doi-access = free }} and associates with adenylyl cyclase. This causes the inactivation of adenylyl cyclase, resulting in a decrease of cAMP produced from ATP, which leads to a decrease of intracellular cAMP. PKA is not able to be activated by cAMP, so proteins such as phosphorylase kinase cannot be phosphorylated by PKA. In particular, phosphorylase kinase is responsible for the phosphorylation and activation of glycogen phosphorylase, an enzyme necessary for glycogen breakdown. Thus in this pathway, the downstream effect of adenylyl cyclase inactivation is decreased breakdown of glycogen.

The relaxation of gastrointestinal tract motility is by presynaptic inhibition,{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=978-0-443-07145-4 }} Page 163 where transmitters inhibit further release by homotropic effects.

;Agonists

{{div col|colwidth=18em}}

• 4-NEMD
• 7-Me-marsanidine (also I₁ agonist)
• Agmatine (also I agonist, NMDA, 5-HT₃, nicotinic antagonist and NOS inhibitor)
• Apraclonidine
• Brimonidine
• Cannabigerol (also acts as a moderate affinity 5-HT_1A receptor antagonist, and low affinity CB1 receptor antagonist).
• Clonidine (also I₁ agonist)
• Detomidine
• Dexmedetomidine
• Fadolmidine
• Guanabenz
• Guanfacine
• Lofexidine
• Marsanidine
• Medetomidine
• Methyldopa
• Mivazerol
• Rilmenidine (also I agonist)
• Romifidine
• Talipexole (also dopamine agonist)
• Tiamenidine
• Tizanidine
• Tolonidine
• Xylazine
• Xylometazoline{{cite journal | vauthors = Haenisch B, Walstab J, Herberhold S, Bootz F, Tschaikin M, Ramseger R, Bönisch H | title = Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline | journal = Fundamental & Clinical Pharmacology | volume = 24 | issue = 6 | pages = 729–739 | date = December 2010 | pmid = 20030735 | doi = 10.1111/j.1472-8206.2009.00805.x | s2cid = 25064699 }}

{{div col end}}

;Partial agonists

{{div col|colwidth=25em}}

• Oxymetazoline (also α₁ agonist)
• TDIQ{{cite journal | vauthors = Young R | title = TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo [4,5-g]isoquinoline): discovery, pharmacological effects, and therapeutic potential | journal = CNS Drug Reviews | volume = 13 | issue = 4 | pages = 405–422 | year = 2007 | pmid = 18078426 | pmc = 6494129 | doi = 10.1111/j.1527-3458.2007.00022.x }}

{{div col end}}

{{div col|colwidth=25em}}

;Inverse agonist

• Caffeine ( and methylxanthines)

{{div col end}}

;Antagonists

{{div col|colwidth=18em}}

• 1-PP (active metabolite of buspirone and gepirone)
• Aripiprazole
• Asenapine
• Atipamezole
• Cirazoline
• Clozapine
• Efaroxan
• Idazoxan
• Lurasidone
• Melperone
• Mianserin
• Mirtazapine
• Napitane
• Olanzapine
• Paliperidone (also primary active metabolite of risperidone)
• Phenoxybenzamine
• Phentolamine
• Piribedil{{cite journal | vauthors = Millan MJ, Cussac D, Milligan G, Carr C, Audinot V, Gobert A, Lejeune F, Rivet JM, Brocco M, Duqueyroix D, Nicolas JP, Boutin JA, Newman-Tancredi A | title = Antiparkinsonian agent piribedil displays antagonist properties at native, rat, and cloned, human alpha(2)-adrenoceptors: cellular and functional characterization | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 297 | issue = 3 | pages = 876–887 | date = June 2001 | pmid = 11356907 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11356907 | access-date = 2013-08-21 | url-status = dead | archive-url = https://web.archive.org/web/20191214105629/http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11356907 | archive-date = 2019-12-14 }}{{cite journal | vauthors = Gobert A, Di Cara B, Cistarelli L, Millan MJ | title = Piribedil enhances frontocortical and hippocampal release of acetylcholine in freely moving rats by blockade of alpha 2A-adrenoceptors: a dialysis comparison to talipexole and quinelorane in the absence of acetylcholinesterase inhibitors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 305 | issue = 1 | pages = 338–346 | date = April 2003 | pmid = 12649387 | doi = 10.1124/jpet.102.046383 | s2cid = 29234876 }}
• Rauwolscine
• Risperidone
• Rotigotine (α_2B antagonist, non-selective)
• Quetiapine
• Norquetiapine (primary active metabolite of quetiapine)
• Setiptiline
• Tolazoline
• Yohimbine
• Ziprasidone
• Zotepine (discontinued)

{{div col end}}

{{main article|alpha-adrenergic agonist}}

Norepinephrine has higher affinity for the α₂ receptor than epinephrine does, and therefore relates less to the latter's functions. Nonselective α₂ agonists include the antihypertensive drug clonidine, which can be used to lower blood pressure and to reduce hot flashes associated with menopause. Clonidine has also been successfully used in indications that exceed what would be expected from a simple blood-pressure lowering drug: it has shown positive results in children with ADHD who have tics resulting from the treatment with a CNS stimulant drug, such as Adderall XR or methylphenidate;National Institute of Neurological Disorders and Stroke (2002). [http://www.ninds.nih.gov/news_and_events/news_articles/news_article_adhd.htm"Methylphenidate and Clonidine Help Children With ADHD and Tics".] clonidine also helps alleviate symptoms of opioid withdrawal.{{cite web | title=Clonidine Oral Uses |url=http://www.webmd.com/drugs/mono-24-CLONIDINE+-+ORAL.aspx?drugid=11754&drugname=Clonidine|publisher=Web MD}} The hypotensive effect of clonidine was initially attributed through its agonist action on presynaptic α₂ receptors, which act as a down-regulator on the amount of norepinephrine released in the synaptic cleft, an example of autoreceptor. However, it is now known that clonidine binds to imidazoline receptors with a much greater affinity than α₂ receptors, which would account for its applications outside the field of hypertension alone. Imidazoline receptors occur in the nucleus tractus solitarii and also the centrolateral medulla. Clonidine is now thought to decrease blood pressure via this central mechanism. Other nonselective agonists include dexmedetomidine, lofexidine (another antihypertensive), TDIQ (partial agonist), tizanidine (in spasms, cramping) and xylazine. Xylazine has veterinary use.

In the European Union, dexmedetomidine received a marketing authorization from the European Medicines Agency (EMA) on August 10, 2012, under the brand name of Dexdor.{{cite web|title=EPAR summary for the public: Dexdomitor|url=http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/veterinary/000070/WC500062498.pdf|website=www.ema.europa.eu/ema/|publisher=European Medicines Agency|access-date=July 22, 2017}} It is indicated for sedation in the ICU for patients needing mechanical ventilation.

In non-human species this is an immobilizing and anesthetic drug, presumptively also mediated by α₂ adrenergic receptors because it is reversed by yohimbine, an α₂ antagonist.

α_2A selective agonists include guanfacine (an antihypertensive) and brimonidine (UK 14,304).

(R)-3-nitrobiphenyline is an α_2C selective agonist as well as being a weak antagonist at the α{{sub|2A}} and α{{sub|2B}} subtypes.{{cite journal | vauthors = Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, Ghelfi F, Giannella M, Paris H, Piergentili A, Quaglia W, Schaak S, Vesprini C, Pigini M | title = Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 16 | pages = 3964–3968 | date = August 2007 | pmid = 17630725 | doi = 10.1021/jm061487a }}{{cite journal | vauthors = Del Bello F, Mattioli L, Ghelfi F, Giannella M, Piergentili A, Quaglia W, Cardinaletti C, Perfumi M, Thomas RJ, Zanelli U, Marchioro C, Dal Cin M, Pigini M | title = Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 21 | pages = 7825–7835 | date = November 2010 | pmid = 20925410 | doi = 10.1021/jm100977d }}

{{main article|alpha blocker}}

Nonselective α blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan (experimental),{{Cite web |url=http://www.online-medical-dictionary.org/Idazoxan.asp?q=Idazoxan |title=online-medical-dictionary.org |access-date=2007-12-26 |archive-url=https://web.archive.org/web/20070824133343/http://www.online-medical-dictionary.org/Idazoxan.asp?q=Idazoxan |archive-date=2007-08-24 |url-status=dead }} and SB-269,970.

Yohimbine is a relatively selective α₂ blocker that has been investigated as a treatment for erectile dysfunction.

Tetracyclic antidepressants mirtazapine and mianserin are also potent α antagonists with mirtazapine being more selective for α₂ subtype (~30-fold selective over α₁) than mianserin (~17-fold).

α_2A selective blockers include BRL-44408 and RX-821,002.

α_2B selective blockers include ARC-239 and imiloxan.

α_2C selective blockers include JP-1302 and spiroxatrine, the latter also being a serotonin 5-HT_1A antagonist.

• Adrenergic receptor

{{Reflist|2}}

• {{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1274 | title = Adrenoceptors | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}

{{G protein-coupled receptors}}

{{Adrenergics}}

{{DEFAULTSORT:Alpha-2 Adrenergic Receptor}}

Category:Adrenergic receptors

Category:Human proteins