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.[3] It is also located on thevascular 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.[3] The α2-adrenergic receptor binds both norepinephrine released bysympathetic postganglionic fibers and epinephrine (adrenaline) released by theadrenal medulla, binding norepinephrine with slightly higher affinity.[4] It has several general functions in common with theα1-adrenergic receptor, but also has specific effects of its own.Agonists (activators) of the α2-adrenergic receptor are frequently used inanaesthesia where they affectsedation, muscle relaxation andanalgesia through effects on thecentral nervous system (CNS).[5]
In the brain, α2-adrenergic receptors can be localized either pre- or post-synaptically, and the majority of receptors appear to be post-synaptic.[6] For example, theα2A adrenergic receptor subtype is post-synaptic in theprefrontal cortex and these receptors strengthen cognitive and executive functions by inhibiting cAMP opening of potassium channels, thus enhancing prefrontal connections and neuronal firing.[7] The α2A-adrenergic agonist,guanfacine, is now used to treat prefrontal cortical cognitive disorders such as attention deficit hyperactivity disorder (ADHD).[8]
Vasoconstriction of arteries toheart (coronary artery);[10] however, the extent of this effect may be limited and may be negated by the vasodilatory effect fromβ2 receptors[11]
The α subunit of an inhibitoryG protein -Gi dissociates from the G protein,[19] and associates withadenylyl cyclase. This causes the inactivation of adenylyl cyclase, resulting in a decrease ofcAMP produced from ATP, which leads to a decrease of intracellular cAMP.PKA is not able to be activated by cAMP, so proteins such asphosphorylase kinase cannot be phosphorylated by PKA. In particular, phosphorylase kinase is responsible for the phosphorylation and activation ofglycogen 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 bypresynaptic inhibition,[16] where transmitters inhibit further release byhomotropic effects.
Norepinephrine has higher affinity for the α2 receptor thanepinephrine does, and therefore relates less to the latter's functions.[16] Nonselective α2 agonists include theantihypertensive drugclonidine,[16] 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 withADHD who havetics resulting from the treatment with aCNS stimulant drug, such asAdderall XR ormethylphenidate;[25] clonidine also helps alleviate symptoms ofopioid withdrawal.[26] 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 thesynaptic cleft, an example ofautoreceptor. However, it is now known that clonidine binds toimidazoline 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 thenucleus tractus solitarii and also thecentrolateral medulla. Clonidine is now thought to decrease blood pressure via this central mechanism. Other nonselective agonists includedexmedetomidine,lofexidine (another antihypertensive),TDIQ (partial agonist),tizanidine (inspasms,cramping) andxylazine. Xylazine hasveterinary use.
In the European Union, dexmedetomidine received a marketing authorization from theEuropean Medicines Agency (EMA) on August 10, 2012, under the brand name ofDexdor.[27] It is indicated for sedation in theICU 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.
α2A selective agonists includeguanfacine (an antihypertensive) and brimonidine (UK 14,304).
Yohimbine[16] is a relatively selective α2 blocker that has been investigated as a treatment for erectile dysfunction.
Tetracyclic antidepressantsmirtazapine andmianserin are also potent α antagonists with mirtazapine being more selective for α2 subtype (~30-fold selective over α1) than mianserin (~17-fold).
α2A selective blockers includeBRL-44408 and RX-821,002.
α2B selective blockers include ARC-239 andimiloxan.
α2C selective blockers include JP-1302 andspiroxatrine, the latter also being aserotonin 5-HT1A antagonist.
^abcdSaunders C, Limbird LE (November 1999). "Localization and trafficking of alpha2-adrenergic receptor subtypes in cells and tissues".Pharmacology & Therapeutics.84 (2):193–205.doi:10.1016/S0163-7258(99)00032-7.PMID10596906.
^abcLevick JR (2000). "Chapter 14.1: Sympathetic vasoconstrictor nerves".Introduction to Cardiovascular Physiology (3rd ed.). Arnold Publishers.
^Boron WF (2012).Medical Physiology: A Cellular and Molecular Approach. p. 360.
^U'Prichard DC, Bechtel WD, Rouot BM, Snyder SH (July 1979). "Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine".Molecular Pharmacology.16 (1):47–60.PMID39248.
^Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, et al. (April 2007). "Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex".Cell.129 (2):397–410.doi:10.1016/j.cell.2007.03.015.PMID17448997.
^Hardman JG, Limbird LE, Gilman AG (2001).Goodman & Gilman's the pharmacological basis of therapeutics (10th ed.). New York: McGraw-Hill. p. 140.ISBN978-0-07-135469-1.
^Woodman OL, Vatner SF (August 1987). "Coronary vasoconstriction mediated by alpha 1- and alpha 2-adrenoceptors in conscious dogs".The American Journal of Physiology.253 (2 Pt 2):H388 –H393.doi:10.1152/ajpheart.1987.253.2.H388.PMID2887122.
^Elliott J (August 1997). "Alpha-adrenoceptors in equine digital veins: evidence for the presence of both alpha1 and alpha2-receptors mediating vasoconstriction".Journal of Veterinary Pharmacology and Therapeutics.20 (4):308–317.doi:10.1046/j.1365-2885.1997.00078.x.PMID9280371.
^Gobert A, Di Cara B, Cistarelli L, Millan MJ (April 2003). "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".The Journal of Pharmacology and Experimental Therapeutics.305 (1):338–346.doi:10.1124/jpet.102.046383.PMID12649387.S2CID29234876.
^Roth BL, Driscol J (12 January 2011)."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived fromthe original on 8 November 2013. Retrieved27 November 2013.
^Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, et al. (August 2007). "Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist".Journal of Medicinal Chemistry.50 (16):3964–3968.doi:10.1021/jm061487a.PMID17630725.
^Del Bello F, Mattioli L, Ghelfi F, Giannella M, Piergentili A, Quaglia W, et al. (November 2010). "Fruitful adrenergic α(2C)-agonism/α(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence".Journal of Medicinal Chemistry.53 (21):7825–7835.doi:10.1021/jm100977d.PMID20925410.
