Alpha-2 adrenergic receptor
The alpha-2 (
Cellular localization
[edit]The
- Brainstem (especially the locus coeruleus as presynaptic & somatodendritic autoreceptor [2])
- Midbrain
- Hypothalamus
- Olfactory system
- Hippocampus
- Spinal cord
- Cerebral cortex
- Cerebellum
- Septum
Whereas the
- Thalamus
- Pyramidal layer of the hippocampus
- Cerebellar Purkinje layer
and the
- Midbrain
- Thalamus
- Amygdala
- Dorsal root ganglia
- Olfactory system
- Hippocampus
- Cerebral cortex
- Basal ganglia
- Substantia nigra
- Ventral tegmentum
Effects
[edit]The
In the brain,
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[9]
- Vasoconstriction of arteries to heart (coronary artery);[10] however, the extent of this effect may be limited and may be negated by the vasodilatory effect from
β 2 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
[edit]Individual actions of the
- Mediates synaptic transmission in pre- and postsynaptic nerve terminals
- Decrease release of acetylcholine[16]
- Decrease release of norepinephrine[16]
- Inhibit norepinephrine system in brain
- 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
[edit]The
The relaxation of gastrointestinal tract motility is by presynaptic inhibition,[16] where transmitters inhibit further release by homotropic effects.
- 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 antagonist, and low affinity CB1 receptor antagonist).
- Clonidine (also I1 agonist)
- Detomidine
- Dexmedetomidine
- Fadolmidine
- Guanabenz
- Guanfacine
- Lofexidine
- Marsanidine
- Medetomidine
- Methyldopa
- Mivazerol
- Rilmenidine (also I agonist)
- Romifidine
- Talipexole (also dopamine agonist)
- Tiamenidine
- Tizanidine
- Tolonidine
- Xylazine
- Xylometazoline[20]
- Partial agonists
- Inverse agonist
- Caffeine ( and methylxanthines)
- Antagonists
- 1-PP (active metabolite of buspirone and gepirone)
- 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 (
α 2B antagonist, non-selective) - Quetiapine
- Norquetiapine (primary active metabolite of quetiapine)
- Setiptiline
- Tolazoline
- Yohimbine
- Ziprasidone
- Zotepine (discontinued)
Drug | 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
[edit]Norepinephrine has higher affinity for the
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.[30] 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
(R)-3-nitrobiphenyline is an
Antagonists
[edit]Nonselective
Yohimbine[16] is a relatively selective
Tetracyclic antidepressants mirtazapine and mianserin are also potent
See also
[edit]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 d 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 (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.
- ^ 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.
- ^ Woodman OL, Vatner SF (1987). "Coronary vasoconstriction mediated by
α 1- andα 2-adrenoceptors in conscious dogs". Am. J. Physiol. 253 (2 Pt 2): H388–93. doi:10.1152/ajpheart.1987.253.2.H388. 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.
- ^ a b Basic & Clinical Pharmacology, 11th Edition, McGraw Hill 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
α 1 andα 2-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
α 1 andα 2 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 978-0-443-07145-4. 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. doi:10.1016/S0022-2275(20)37319-3. PMID 6119348.
- ^ a b Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 978-0-87893-725-7.
- ^ 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.
- ^ 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. S2CID 25064699.
- ^ 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.
{{cite journal}}
: CS1 maint: numeric names: authors list (link) - ^ 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. Archived from the original on 2019-12-14. Retrieved 2013-08-21.
- ^ 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. 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]
- ^ "Therapeutic Goods Administration – Home page". 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.
- ^ 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.
- ^ 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
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. PMID 20925410. - ^ "online-medical-dictionary.org". Archived from the original on 2007-08-24. Retrieved 2007-12-26.
External links
[edit]- "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.