Alpha-2 adrenergic receptor
The alpha-2 (α2) adrenergic receptor (or adrenoceptor) is a
Cellular localization
The α2A adrenergic receptor is localised in the following central nervous system (CNS) structures:[2]
- Brainstem (especially the locus coeruleus as presynaptic & somatodendritic autoreceptor [2])
- Midbrain
- Hypothalamus
- Olfactory system
- Hippocampus
- Spinal cord
- Cerebral cortex
- Cerebellum
- Septum
Whereas the α2B adrenergic receptor is localised in the following CNS structures:[2]
- 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
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.
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, the α2A 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.[7] The α2A-adrenergic agonist, guanfacine, is now used to treat prefrontal cortical cognitive disorders such as attention deficit hyperactivity disorder (ADHD).[8]
General
Common effects include:
- Suppression of release of noradrenaline) by negative feedback[3]
- Transient hypertension (increase in blood pressure), followed by a sustained hypotension (decrease in blood pressure)[5]
- arteries[9]
- Vasoconstriction of arteries to coronary artery);[10] however, the extent of this effect may be limited and may be negated by the vasodilatory effect from β2 receptors[11]
- Constriction of some vascular smooth muscle[12]
- Venoconstriction of veins[13]
- Decrease motility of smooth muscle in gastrointestinal tract[14]
- Inhibition of lipolysis[12]
- Facilitation of the cognitive functions associated with the prefrontal cortex (PFC; working memory, attention, executive functioning, etc.)[15]
- Sedation[15]
- Analgesia
Individual
Individual actions of the α2 receptor include:
- Mediates synaptic transmission in pre- and postsynaptic nerve terminals
- Decrease release of acetylcholine[16]
- Decrease release of norepinephrine[16]
- Inhibit norepinephrine systemin brain
- Inhibit
- Inhibition[17] of lipolysis in adipose tissue[18]
- Inhibition of insulin release in pancreas[18]
- 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 - Gi dissociates from the G protein,[19] 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
- Agonists
- 4-NEMD
- agonist)
- inhibitor)
- Apraclonidine
- Brimonidine
- CB1 receptor antagonist).
- agonist)
- Detomidine
- Dexmedetomidine
- Fadolmidine
- Guanabenz
- Guanfacine
- Lofexidine
- Marsanidine
- Medetomidine
- Methyldopa
- Mivazerol
- agonist)
- Romifidine
- Talipexole (also dopamine agonist)
- Tiamenidine
- Tizanidine
- Tolonidine
- Xylazine
- Xylometazoline[20]
- Partial agonists
- Antagonists
- )
- Aripiprazole
- Asenapine
- Atipamezole
- Cirazoline
- Clozapine
- Efaroxan
- Idazoxan
- Lurasidone
- Melperone
- Mianserin
- Mirtazapine
- Napitane
- Olanzapine
- Paliperidone (also primary active metabolite of risperidone)
- Phenoxybenzamine
- Phentolamine
- Piribedil[22][23]
- Rauwolscine
- Risperidone
- Rotigotine (α2B antagonist, non-selective)
- Quetiapine
- Norquetiapine (primary active metabolite of quetiapine)
- Setiptiline
- Tolazoline
- Yohimbine
- Ziprasidone
- Zotepine (discontinued)
| 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 | 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 | ? | ? | ? | ? |
| 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
In the European Union, dexmedetomidine received a marketing authorization from the
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).
Antagonists
Nonselective
Yohimbine[16] 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).
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
References
- PMID 12949138.
- ^ 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.
- ^ PMID 10215710.
- ^ Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine. Mol Pharmacol. 16: 47-60, 1979.
- ^ Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129: 397–410, 2007.
- ^ Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species. Neurobiol Learn Mem. 176: 107327, 2020.
- ^ Goodman Gilman, Alfred. Goodman & Gilman's The Pharmacological Basis of Therapeutics. Tenth Edition. McGraw-Hill (2001): Page 140.
- PMID 2887122.
- PMID 12147535.
- ^ a b Basic & Clinical Pharmacology, 11th Edition, McGraw Hill LANGE, Katzung Betram G.; Chapter 9. Adrenoceptor Agonists & Sympathomimetic Drugs
- PMID 9280371.
- PMID 2889649.
- ^ a b Arnsten, AFT (26 July 2007). "Alpha-2 Agonists in the Treatment of ADHD". Medscape Psychiatry. WebMD. Retrieved 13 November 2013.
- ^ ISBN 978-0-443-07145-4. Page 163
- PMID 6119348.
- ^ ISBN 978-0-87893-725-7.
- PMID 18434433.
- ^ S2CID 25064699.
- PMID 18078426.)
{{cite journal}}: CS1 maint: numeric names: authors list (link - PMID 11356907. Archived from the originalon 2019-12-14. Retrieved 2013-08-21.
- S2CID 29234876.
- ^ 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.
- ^ "Medscape Multispecialty – Home page". WebMD. Retrieved 27 November 2013.[full citation needed]
- Department of Health (Australia). Retrieved 27 November 2013.[full citation needed]
- ^ "Daily Med – Home page". U.S. National Library of Medicine. Retrieved 27 November 2013.[full citation needed]
- ^ National Institute of Neurological Disorders and Stroke (2002). "Methylphenidate and Clonidine Help Children With ADHD and Tics".
- ^ "Clonidine Oral Uses". Web MD.
- ^ "EPAR summary for the public: Dexdomitor" (PDF). www.ema.europa.eu/ema/. European Medicines Agency. Retrieved July 22, 2017.
- PMID 17630725.
- PMID 20925410.
- ^ "online-medical-dictionary.org". 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.