Alpha-2 adrenergic receptor

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The alpha-2 (α2) adrenergic receptor (or adrenoceptor) 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.[1] Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

Cellular localization

The α2A adrenergic receptor is localised in the following central nervous system (CNS) structures:[2]

Whereas the α2B adrenergic receptor is localised in the following CNS structures:[2]

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

and the α2C adrenergic receptor is localised in the CNS structures:[2]

  • 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.[3] 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.[3] 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.[4] 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 veterinary anaesthesia where they affect sedation, muscle relaxation and analgesia through effects on the central nervous system (CNS).[5]


Common effects include:


Individual actions of the α2 receptor include:

Signaling cascade

The α subunit of an inhibitory G protein - Gi dissociates from the G protein,[16] 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,[13] where transmitters inhibit further release by homotropic effects.


Partial agonists
Binding affinity (Ki in nM) and clinical data on a number of alpha-2 ligands[22][23][24][25]
Drug α1A α1B α1D α2A α2B α2C Indication(s) Route of Administration Bioavailability Elimination half-life Metabolising enzymes Protein binding
Clonidine 316.23 316.23 125.89 42.92 106.31 233.1 Hypertension, ADHD, analgesia, sedation Oral, epidural, transdermal 75-85% (IR), 89% (XR) 12-16 h CYP2D6 20-40%
Dexmedetomidine 199.53 316.23 79.23 6.13 18.46 37.72 Procedural and ICU sedation IV 100% 6 minutes 94%
Guanfacine ? ? ? 71.81 1200.2 2505.2 Hypertension, ADHD Oral 80-100% (IR), 58% (XR) 17 h (IR), 18 h (XR) CYP3A4 70%
Xylazine ? ? ? 5754.4 3467.4 >10000 Veterinary sedation ? ? ? ? ?
Xylometazoline ? ? ? 15.14 1047.13 128.8 Nasal congestion Intranasal ? ? ? ?
Asenapine 1.2 ? ? 1.2 0.32 1.2 Schizophrenia, bipolar disorder Sublingual 35% 24 h CYP1A2 & UGT1A4 95%
Clozapine 1.62 7 ? 37 25 6 Treatment-resistant schizophrenia Oral 50-60% 12 h CYP1A2, CYP3A4, CYP2D6 97%
Mianserin 74 ? ? 4.8 27 3.8 Depression Oral 20% 21-61 h CYP3A4 95%
Mirtazapine 500 ? ? 20 ? 18 Depression Oral 50% 20-40 h CYP1A2, CYP2D6, CYP3A4 85%


Norepinephrine has higher affinity for the α2 receptor than has epinephrine, and therefore relates less to the latter's functions.[13] Nonselective α2 agonists include the antihypertensive drug clonidine,[13] 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 recently shown positive results in children with ADHD who suffer from tics resulting from the treatment with a CNS stimulant drug, such as Adderall XR or methylphenidate;[26] clonidine also helps alleviate symptoms of opioid withdrawal.[27] 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.[28] 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.

α2A selective agonists include guanfacine (an antihypertensive) and Brimonidine (UK 14,304).

(R)-3-nitrobiphenyline is an α2C selective agonist as well as being a weak antagonist at the α2A and α2B subtypes.[29][30]


Nonselective α blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan*[13](experimental),[31] and SB-269,970.

Yohimbine*[13] is a relatively selective alpha-2 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).

α2A selective blockers include BRL-44408 and RX-821,002.

α2B selective blockers include ARC-239 and imiloxan.

α2C selective blockers include JP-1302 and spiroxatrine, the latter also being a serotonin 5-HT1A antagonist.

See also


  1. ^ Ruuskanen JO, Xhaard H, Marjamäki A, Salaneck E, Salminen T, Yan YL, Postlethwait JH, Johnson MS, Larhammar D, Scheinin M (January 2004). "Identification of duplicated fourth alpha2-adrenergic receptor subtype by cloning and mapping of five receptor genes in zebrafish". Molecular Biology and Evolution. 21 (1): 14–28. doi:10.1093/molbev/msg224. PMID 12949138.
  2. ^ a b c Saunders, 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. PMID 10596906.
  3. ^ a b c Cardiovascular Physiology, 3rd Edition, Arnold Publishers, Levick, J.R., Chapter 14.1, Sympathetic vasoconstrictor nerves
  4. ^ Boron, Walter F. (2012). Medical Physiology: A Cellular and Molecular Approach. p. 360.
  5. ^ a b c Khan, ZP; Ferguson, CN; Jones, RM (February 1999). "alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role". Anaesthesia. 54 (2): 146–65. doi:10.1046/j.1365-2044.1999.00659.x. PMID 10215710.
  6. ^ Goodman Gilman, Alfred. Goodman & Gilman's The Pharmacological Basis of Therapeutics. Tenth Edition. McGraw-Hill (2001): Page 140.
  7. ^ Woodman OL, Vatner SF (1987). "Coronary vasoconstriction mediated by α1- and α2-adrenoceptors in conscious dogs". Am. J. Physiol. 253 (2 Pt 2): H388–93. doi:10.1152/ajpheart.1987.253.2.H388. PMID 2887122.
  8. ^ Sun, D.; Huang, A.; Mital, S.; Kichuk, M. R.; Marboe, C. C.; Addonizio, L. J.; Michler, R. E.; Koller, A.; Hintze, T. H.; Kaley, G. (2002). "Norepinephrine elicits beta2-receptor-mediated dilation of isolated human coronary arterioles". Circulation. 106 (5): 550–555. doi:10.1161/01.CIR.0000023896.70583.9F. PMID 12147535.
  9. ^ a b Basic & Clinical Pharmacology, 11th Edition, McGrawHill LANGE, Katzung Betram G.; Chapter 9. Adrenoceptor Agonists & Sympathomimetic Drugs
  10. ^ Elliott J (1997). "Alpha-adrenoceptors in equine digital veins: evidence for the presence of both α1 and α2-receptors mediating vasoconstriction". J. Vet. Pharmacol. Ther. 20 (4): 308–17. doi:10.1046/j.1365-2885.1997.00078.x. PMID 9280371.
  11. ^ Sagrada A, Fargeas MJ, Bueno L (1987). "Involvement of α1 and α2 adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat". Gut. 28 (8): 955–9. doi:10.1136/gut.28.8.955. PMC 1433140. PMID 2889649.
  12. ^ a b Arnsten, AFT (26 July 2007). "Alpha-2 Agonists in the Treatment of ADHD". Medscape Psychiatry. WebMD. Retrieved 13 November 2013.
  13. ^ a b c d e f g Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. Page 163
  14. ^ Wright EE, Simpson ER (1981). "Inhibition of the lipolytic action of beta-adrenergic agonists in human adipocytes by alpha-adrenergic agonists". J. Lipid Res. 22 (8): 1265–70. doi:10.1016/S0022-2275(20)37319-3. PMID 6119348. Archived from the original on 2009-03-23. Retrieved 2007-12-01.
  15. ^ a b Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 978-0-87893-725-7.
  16. ^ Kou Qin; Pooja R. Sethi; Nevin A. Lambert (August 2008). "Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins". The FASEB Journal. 22 (8): 2920–2927. doi:10.1096/fj.08-105775. PMC 2493464. PMID 18434433.
  17. ^ "Methamphetamine – Targets". DrugBank. University of Alberta. 8 February 2013. Retrieved 31 December 2013.
  18. ^ a b Haenisch, B.; Walstab, J.; Herberhold, S.; Bootz, F.; Tschaikin, M.; Ramseger, R.; Bönisch, H. (2009). "Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline". Fundamental & Clinical Pharmacology. 24 (6): 729–739. doi:10.1111/j.1472-8206.2009.00805.x. PMID 20030735.
  19. ^ Young, R; CNS Drug Rev. (2007); et al. (2007). "TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo [4,5-g]isoquinoline): discovery, pharmacological effects, and therapeutic potential". CNS Drug Reviews. 13 (4): 405–22. doi:10.1111/j.1527-3458.2007.00022.x. PMC 6494129. PMID 18078426.
  20. ^ Millan MJ, Cussac D, Milligan G, et al. (June 2001). "Antiparkinsonian agent piribedil displays antagonist properties at native, rat, and cloned, human alpha(2)-adrenoceptors: cellular and functional characterization". The Journal of Pharmacology and Experimental Therapeutics. 297 (3): 876–87. PMID 11356907.
  21. ^ 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): 338–46. doi:10.1124/jpet.102.046383. PMID 12649387.
  22. ^ 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 from the original on 8 November 2013. Retrieved 27 November 2013.
  23. ^ "Medscape Multispecialty – Home page". WebMD. Retrieved 27 November 2013.[full citation needed]
  24. ^ "Therapeutic Goods Administration – Home page". Department of Health (Australia). Retrieved 27 November 2013.[full citation needed]
  25. ^ "Daily Med – Home page". U.S. National Library of Medicine. Retrieved 27 November 2013.[full citation needed]
  26. ^ National Institute of Neurological Disorders and Stroke (2002). "Methylphenidate and Clonidine Help Children With ADHD and Tics".
  27. ^ "Clonidine Oral Uses". Web MD.
  28. ^ "EPAR summary for the public: Dexdomitor" (PDF). European Medicines Agency. Retrieved July 22, 2017.
  29. ^ 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 (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): 3964–8. doi:10.1021/jm061487a. PMID 17630725.
  30. ^ Del Bello, Fabio; Mattioli, Laura; Ghelfi, Francesca; Giannella, Mario; Piergentili, Alessandro; Quaglia, Wilma; Cardinaletti, Claudia; Perfumi, Marina; Thomas, Russell J.; Zanelli, Ugo; Marchioro, Carla; Dal Cin, Michele; Pigini, Maria (11 November 2010). "Fruitful Adrenergic α2C-Agonism/α2A-Antagonism Combination to Prevent and Contrast Morphine Tolerance and Dependence". Journal of Medicinal Chemistry. 53 (21): 7825–7835. doi:10.1021/jm100977d. PMID 20925410.
  31. ^ "". Archived from the original on 2007-08-24. Retrieved 2007-12-26.

External links

  • "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.