Alpha-2 adrenergic receptor

The alpha-2 (α₂) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the G_i heterotrimeric G-protein. It consists of three highly homologous subtypes, including α_2A-, α_2B-, and α_2C-adrenergic. Some species other than humans express a fourth α_2D-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 localisation

The 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

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 (noradrenaline) 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

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

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

The α subunit of an inhibitory G protein - G_i dissociated 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.

Ligands

Agonists 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-HT1A receptor agonist, and low affinity CB1 receptor antagonist). Clonidine (also I1 agonist) Detomidine Dexmedetomidine Fadolmidine Guanabenz Guanfacine Lofexidine Marsanidine Medetomidine Methamphetamine[17] Mivazerol Rilmenidine (also I agonist) Romifidine Talipexole (also dopamine agonist) Tiamenidine Tizanidine Tolonidine Xylazine Xylometazoline[18]

Partial agonists Oxymetazoline (also α1 agonist)[18] TDIQ[19]

Antagonists Aripiprazole Asenapine Atipamezole Cirazoline Clozapine Efaroxan Idazoxan Lurasidone Melperone Mianserin Mirtazapine Napitane Olanzapine Paliperidone (also primary active metabolite of Risperidone) Phenoxybenzamine Phentolamine Piribedil[20][21] Rauwolscine Risperidone Rotigotine (α2B antagonist, non-selective) Quetiapine Norquetiapine (primary active metabolite of Quetiapine) Setiptiline Tolazoline Yohimbine Ziprasidone Zotepine (discontinued)

Binding affinity (K_i 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
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	Veterinary sedation	?	?	?	?	?
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

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;^[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 08/10/2012 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.

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

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

Antagonists

Nonselective α blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan*^[13](experimental),^[29] 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.

See also

• Adrenergic receptor

References

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4. Boron, Walter F. (2012). Medical Physiology: A Cellular and Molecular Approach. p. 360.
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6. Goodman Gilman, Alfred. Goodman & Gilman's The Pharmacological Basis of Therapeutics. Tenth Edition. McGraw-Hill (2001): Page 140.
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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. 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. Arnsten, AFT (26 July 2007). "Alpha-2 Agonists in the Treatment of ADHD". Medscape Psychiatry. WebMD. Retrieved 13 November 2013.
13. Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 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. PMID 6119348.
15. Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
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17. "Methamphetamine – Targets". DrugBank. University of Alberta. 8 February 2013. Retrieved 31 December 2013.
18. 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." 13 (4): 405–22. doi:10.1111/j.1527-3458.2007.00022.x. 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 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.
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24. "Therapeutic Goods Administration – Home page". Department of Health (Australia). Retrieved 27 November 2013.
25. "Daily Med – Home page". U.S. National Library of Medicine. Retrieved 27 November 2013.
26. National Institute of Neurological Disorders and Stroke (2002). "Methylphenidate and Clonidine Help Children With ADHD and Tics".
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28. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/veterinary/000070/WC500062498.pdf
29. online-medical-dictionary.org

External links

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