WordNet

first in order of importance; "the alpha male in the group of chimpanzees"; "the alpha star in a constellation is the brightest or main star"
the 1st letter of the Greek alphabet
the beginning of a series or sequence; "the Alpha and Omega, the first and the last, the beginning and the end"--Revelations
early testing stage of a software or hardware product; "alpha version"
a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response
any high mountain

PrepTutorEJDIC

アルファ(ギリシア語アルファベットの第1字A,α;英語のA,aに相当) / アルファ星(星座の主星)
=sense organ / 受信装置
高山,高峰

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/12/12 15:34:04」(JST)

wiki en

[Wiki en表示]

Cellular localisation[edit]

α_2A adrenergic receptor is localised in the following central nervous system (CNS) structures:^[2]

Brainstem (especially the locus coeruleus)
Midbrain
Hypothalamus
Hippocampus
Spinal cord
Cerebral cortex
Cerebellum
Septum

Whereas the α_2B adrenergic receptor is localised in the following CNS structures:^[2]

Olfactory system
Thalamus
Pyramidal layer of the hippocampus
Cerebellar purkinje layer

and the α_2C 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

Effects[edit]

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]

General[edit]

Common effects include:

Suppression of release of norepinephrine (noradrenaline) by negative feedback.^[3]
Transient hypertension (increase in blood pressure), followed by a sustained hypotension (decrease in blood pressure).^[5]
Vasoconstriction of certain arteries^[6]
Vasoconstriction of arteries to heart (coronary artery)^[7] however the extent of this effect may be limited and may be negated by the vasodilatory effect from β₂ receptors^[8]
Constriction of some vascular smooth muscle^[9]
Venoconstriction of veins^[10]
Decrease motility of smooth muscle in gastrointestinal tract^[11]
Inhibition of lipolysis^[9]
Facilitation of the cognitive functions associated with the prefrontal cortex (PFC; working memory, attention, executive functioning, etc.)^[12]
Sedation^[12]
Analgesia

Individual[edit]

Individual actions of the α₂ receptor include:

Mediates synaptic transmission in pre- and postsynaptic nerve terminals
- Decrease release of acetylcholine^[13]
- Decrease release of norepinephrine^[13]
  - Inhibit norepinephrine system in brain
Inhibition^[14] of lipolysis in adipose tissue^[15]
Inhibition of insulin release in pancreas^[15]
Induction of glucagon release from pancreas
platelet aggregation
Contraction of sphincters of the gastrointestinal tract
Decreased secretion from salivary gland^[5]
Relax gastrointestinal tract (presynaptic effect)
Decreased aqueous humor fluid production from the ciliary body

Signaling cascade[edit]

The α subunit of an inhibitory G protein - G_i dissociated from the G protein, and associates with adenyl cyclase (also known as adenylate cyclase or adenylyl cyclase). This causes the inactivation of adenyl cyclase, resulting in a decrease of cAMP produced from ATP. This leads to a decrease of intracellular cAMP. Protein Kinase A 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 adenyl 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.

Ligands[edit]

Agonists

Apraclonidine
Brimonidine
Clonidine
Desvenlafaxine
Detomidine
Dexmedetomidine
Guanabenz
Guanfacine
Lofexidine
Medetomidine
Romifidine
Tizanidine
Tolonidine
Xylazine
Fadolmidine
Xylometazoline^[16]
Oxymetazoline^[16] (partial α₂ agonist)

Antagonists

Asenapine
Atipamezole
Cirazoline
Clozapine
Efaroxan
Idazoxan
Mianserin
Mirtazapine
Napitane
Paliperidone
Phenoxybenzamine
Phentolamine
Piribedil^[17]^[18]
Rauwolscine
Risperidone
Setiptiline
Tolazoline
Yohimbine

Binding affinity (K_i in nM) and clinical data on a number of alpha-2 ligands^[19]^[20]^[21]^[22]

Drug	α_1A	α_1B	α_1D	α_2A	α_2B	α_2C	Indication(s)	Route of Administration	Bioavailability	Elimination half-life	Metabolising enzymes	Protein binding
Agonists
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	?	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	?	?	?	?	?	?
Xylometazoline	?	?	?	15.14	1047.13	128.8	Nasal congestion	Intranasal	?	?	?	?
Antagonists
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%

Agonists[edit]

Norepinephrine has higher affinity for the α₂ receptor than has epinephrine, and therefore relates less to the latter's functions.^[13] Nonselective agonists include the antihypertensive drug clonidine,^[13] used to lower blood pressure and hot flashes associated with menopausal symptoms. 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;^[23] clonidine also helps alleviate symptoms of opioid withdrawal.^[24] 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), UK-14,304 and xylazine. Xylazine has veterinary use.

In the European Union, dexmedetomidine received a marketing authorization from the European Medicines Agency (EMA) on 08/10/2012 under the brand name of Dexdor.^[25] 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 octopamine, which is also a β₃ agonist.

(R)-3-nitrobiphenyline is an α_2C selective agonist.

Antagonists[edit]

Nonselective α blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan*^[13](experimental),^[26] SB-269,970 and yohimbine*^[13] (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.

References[edit]

^ 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.
^ ^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.
^ ^a ^b ^c Cardiovascular Physiology, 3rd Edition, Arnold Publishers, Levick, J.R., Chapter 14.1, Sympathetic vasoconstrictor nerves
^ Boron, Walter F. (2012). Medical Physiology: A Cellular and Molecular Approach. p. 360.
^ ^a ^b ^c Khan, ZP; Ferguson, CN; Jones, RM (1999 Feb). "alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role.". Anaesthesia 54 (2): 146–65. PMID 10215710. Check date values in: |date= (help)
^ Goodman Gilman, Alfred. Goodman & Gilman's The Pharmacological Basis of Therapeutics. Tenth Edition. McGraw-Hill (2001): Page 140.
^ 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. PMID 2887122.
^ 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. edit
^ ^a ^b Basic & Clinical Pharmacology, 11th Edition, McGrawHill LANGE, Katzung Betram G.; Chapter 9. Adrenoceptor Agonists & Sympathomimetic Drugs
^ 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.
^ 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.
^ ^a ^b Arnsten, AFT (26 July 2007). "Alpha-2 Agonists in the Treatment of ADHD". Medscape Psychiatry. WebMD. Retrieved 13 November 2013.
^ ^a ^b ^c ^d ^e ^f ^g Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 163
^ 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. PMID 6119348.
^ ^a ^b Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
^ ^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. edit
^ 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.
^ 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.
^ Roth, BL; Driscol, J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 27 November 2013.
^ "[Drug Name]". Medscape Reference. WebMD. Retrieved 27 November 2013.
^ "[Drug Name]" (PDF). TGA eBusiness Services. [Drug sponsor]. [Page date]. Retrieved 27 November 2013. Check date values in: |date= (help)
^ "[Drug name]". DailyMed. [Drug sponsor]. page date. Retrieved 27 November 2013. Check date values in: |date= (help)
^ National Institute of Neurological Disorders and Stroke (2002). "Methylphenidate and Clonidine Help Children With ADHD and Tics".
^ "Clonidine Oral Uses". Web MD.
^ http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/veterinary/000070/WC500062498.pdf
^ online-medical-dictionary.org

External links[edit]

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

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 昇圧剤および強心剤の使用 use of vasopressors and inotropes
2. タモキシフェンによるホルモン療法を受ける女性の不正子宮出血と子宮の病理 abnormal uterine bleeding and uterine pathology in women on tamoxifen therapy
3. Eosinophil biology and causes of eosinophilia
4. 選択的エストロゲン受容体モジュレーター・受容体ダウンレギュレーターの作用機序 mechanisms of action of selective estrogen receptor modulators and down regulators
5. 複合免疫不全 combined immunodeficiencies

English Journal

Novel technique to determine the pKA of clonidine at prejunctional α2-adrenoceptors in cardiac and vascular sympathetic transmission.

Angus JA1, Rajasekaran P2, Wright CE3.
European journal of pharmacology.Eur J Pharmacol.2017 Apr 5;800:81-95. doi: 10.1016/j.ejphar.2017.02.030. Epub 2017 Feb 17.
PMID 28219708

Dexmedetomidine use in the ED for control of methamphetamine-induced agitation.

Lam RP1, Yip WL2, Wan CK2, Tsui MS2.
The American journal of emergency medicine.Am J Emerg Med.2017 Apr;35(4):665.e1-665.e4. doi: 10.1016/j.ajem.2016.11.004. Epub 2016 Nov 3.
PMID 27842924

Milk Fat Globule-EGF Factor 8, Secreted by Mesenchymal Stem Cells, Protects Against Liver Fibrosis in Mice.

An SY1, Jang YJ1, Lim HJ1, Han J1, Lee J1, Lee G1, Park JY1, Park SY1, Kim JH2, Do BR2, Han C3, Park HK4, Kim OH5, Song MJ6, Kim SJ5, Kim JH7.
Gastroenterology.Gastroenterology.2017 Apr;152(5):1174-1186. doi: 10.1053/j.gastro.2016.12.003. Epub 2016 Dec 9.
PMID 27956229