Ketanserin: Difference between revisions
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{{Short description|Antihypertensive agent}} |
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{{drugbox |
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{{cs1 config|name-list-style=vanc}} |
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| verifiedrevid = 414566780 |
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{{Drugbox |
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| IUPAC_name = 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1''H'',3''H'')-dione |
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| Verifiedfields = verified |
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| image = Ketanserin.png |
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| Watchedfields = verified |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| verifiedrevid = 420466712 |
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| IUPAC_name = 3-<nowiki/>{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1''H'',3''H'')-dione |
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| image = Ketanserin.png |
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| width = 250px |
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| image2 = Ketanserin_3D.png |
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| width2 = 235px |
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<!--Clinical data--> |
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| tradename = Sufrexal |
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| Drugs.com = {{drugs.com|international|ketanserin}} |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = |
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| legal_status = Rx-only |
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| routes_of_administration = [[Oral administration|Oral]] |
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<!--Pharmacokinetic data--> |
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| bioavailability = 50%<ref name="Wolverton2007">{{cite book | vauthors = Wolverton SE | date = 8 March 2007 | title = Comprehensive Dermatologic Drug Therapy | edition = 2 | publisher = Elsevier Health Sciences | pages = | isbn = 978-1-4377-2070-9 | url = https://books.google.com/books?id=AaJwq_X6U6MC&pg=PT1157}}</ref><ref name="SaitōMinami1992" /> |
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| protein_bound = 95.0% (mainly [[human serum albumin|albumin]]<ref name="SaitōMinami1992" /> |
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| metabolism = |
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| elimination_half-life = 10–29 hours<ref name="ColdDahl2013">{{cite book | vauthors = Cold GE, Dahl BL | date = 11 November 2013 | title = Topics in Neuroanaesthesia and Neurointensive Care: Experimental and Clinical Studies upon Cerebral Circulation, Metabolism and Intracranial Pressure | publisher = Springer Science & Business Media | pages = 193– | isbn = 978-3-662-04845-0 | oclc = 1076237896 | url = https://books.google.com/books?id=cYnqCAAAQBAJ&pg=PA193}}</ref><ref name="Wolverton2007" /><ref name="SaitōMinami1992">{{cite book | editor1 = Hideya Saitō | editor2 = Masaru Minami | date = 1992 | title = Antihypertensive Drugs Today | publisher = VSP | pages = 191– | isbn = 978-90-6764-140-1 | oclc = 231351327 | url = https://books.google.com/books?id=PghVgVDfF7UC&pg=PA191}}</ref> |
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| excretion = |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 74050-98-9 |
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| ATC_prefix = C02 |
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| ATC_suffix = KD01 |
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| ATC_supplemental = {{ATCvet|D03|AX90}} |
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| PubChem = 3822 |
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| IUPHAR_ligand = 88 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB12465 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 3690 |
| ChemSpiderID = 3690 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 97F9DE4CT4 |
| UNII = 97F9DE4CT4 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| InChI = 1/C22H22FN3O3/c23-17-7-5-15(6-8-17)20(27)16-9-11-25(12-10-16)13-14-26-21(28)18-3-1-2-4-19(18)24-22(26)29/h1-8,16H,9-14H2,(H,24,29) |
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| KEGG = D02363 |
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| InChIKey = FPCCSQOGAWCVBH-UHFFFAOYAA |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| smiles = c1ccc2c(c1)c(=O)n(c(=O)[nH]2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F |
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| ChEBI = 6123 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 51 |
| ChEMBL = 51 |
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| synonyms = R41468; R-41468; R-41,468 |
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<!--Chemical data--> |
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| C=22 | H=22 | F=1 | N=3 | O=3 |
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| SMILES = c1ccc2c(c1)c(=O)n(c(=O)[nH]2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C22H22FN3O3/c23-17-7-5-15(6-8-17)20(27)16-9-11-25(12-10-16)13-14-26-21(28)18-3-1-2-4-19(18)24-22(26)29/h1-8,16H,9-14H2,(H,24,29) |
| StdInChI = 1S/C22H22FN3O3/c23-17-7-5-15(6-8-17)20(27)16-9-11-25(12-10-16)13-14-26-21(28)18-3-1-2-4-19(18)24-22(26)29/h1-8,16H,9-14H2,(H,24,29) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = FPCCSQOGAWCVBH-UHFFFAOYSA-N |
| StdInChIKey = FPCCSQOGAWCVBH-UHFFFAOYSA-N |
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| CAS_number = 74050-98-9 |
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| ATC_prefix = C02 |
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| ATC_suffix = KD01 |
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| ATC_supplemental = {{ATCvet|D03|AX90}} |
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| PubChem = 3822 |
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| IUPHAR_ligand = 197 |
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| IUPHAR_ligand = 88 |
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| DrugBank = |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D02363 |
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| chemical_formula = |
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| C=22|H=22|F=1|N=3|O=3 |
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| molecular_weight = 395.43 g/mol |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category= |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_status = |
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| routes_of_administration = |
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}} |
}} |
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'''Ketanserin''' is a drug with affinity for multiple G protein-coupled receptors ([[GPCR]]). Initially it was believed to be a highly selective antagonist for serotonin [[5-HT2A receptor|5-HT<sub>2A</sub>]] receptors, however this is not true. Ketanserin only has good selectivity for [[5-HT2A receptor|5-HT<sub>2A</sub>]] receptors over [[5-HT2C receptor|5-HT<sub>2C</sub>]] receptors (~20-30 fold). Ketanserin also has high affinity for [[alpha-1 adrenergic receptor|alpha-1 adrenergic]] receptors, and very high affinity for [[histamine H1 receptor|histamine H1]] |
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receptors. Therefore, ketanserin can not be used to reliably discriminate between the effects of 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors when both are present in an experimental system. Furthermore, when alpha-1 and H1 receptors are present, the effects of ketanserin can potentially represent a complex interaction of serotonin, adrenergic, and histamine receptor systems. Complicating the matter further is the fact that ketanserin has moderate affinity for [[alpha-2 adrenergic receptor|alpha-2 adrenergic]] (~200 nM) and [[5-HT6 receptor|5-HT<sub>6</sub>]] (~300 nM) receptors as well as weak affinity for dopamine [[dopamine D1 receptor|D1]] and [[dopamine D2 receptor|D2]] receptors (~300 nM and ~500 nM respectively). Ketanserin at levels of 500 nM or greater are thus potentially affecting at least 8 different GPCRs from 4 different families. (All affinity levels taken from the NIMH Psychoactive Drug Screening Program database <ref>[http://pdsp.med.unc.edu/ NIMH Psychoactive Drug Screening Program]</ref>) |
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'''Ketanserin''' ([[International Nonproprietary Name|INN]], [[United States Adopted Name|USAN]], [[British Approved Name|BAN]]) (brand name '''Sufrexal'''; former developmental code name '''R41468''') is a [[drug]] used clinically as an [[antihypertensive agent]] and in [[scientific research]] to study the [[Serotonin|serotonergic system]]; specifically, the [[5-HT2 receptor|5-HT<sub>2</sub> receptor family]].<ref name="Ahuja2005">{{cite book| vauthors = O'Donnell J, Ahuja GD |title=Drug Injury: Liability, Analysis, and Prevention|url=https://books.google.com/books?id=EB00rD8AqaYC&pg=PA304|year=2005|publisher=Lawyers & Judges Publishing Company|isbn=978-0-913875-27-8|pages=304–}}</ref> It was discovered at [[Janssen Pharmaceutica]] in 1980.<ref name="Healy2009">{{cite book| vauthors = Healy D |title=The Creation of Psychopharmacology|url=https://books.google.com/books?id=6O2rPJnyhj0C&pg=PA252|date=1 July 2009|publisher=Harvard University Press|isbn=978-0-674-03845-5|pages=252–253}}</ref><ref name="Schwartz1989">{{cite book| vauthors = Schwartz H |title=Breakthrough: the discovery of modern medicines at Janssen |url=https://archive.org/details/breakthroughdisc0000schw|url-access=registration|date=August 1989|publisher=Skyline Pub. Group|isbn=978-1-56019-100-1|page=[https://archive.org/details/breakthroughdisc0000schw/page/74 74]}}</ref> It is not available in the [[United States]].<ref name="Wolverton2007" /> |
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Receptors for which ketanserin has high affinity binding: |
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*5-HT<sub>2A</sub> = 2-3 nM (rat and human) |
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*5-HT<sub>2C</sub> = 50 nM (rat), 100 nM (human) |
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*alpha-1 adrenergic = ~40 nM |
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*Histamine H1 = 2 nM |
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Ketanserin was discovered at [[Janssen Pharmaceutica]] in 1980. |
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==Uses== |
==Uses== |
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===Antihypertensive=== |
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It is classified as an [[antihypertensive]] by the [[World Health Organization]]<ref>[http://www.whocc.no/atc_ddd_index/?code=C02KD01 ATC/DDD Index<!-- Bot generated title -->]</ref> and the [[National Institute of Health]].<ref>[http://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?mode=&term=Ketanserin Ketanserin<!-- Bot generated title -->]</ref> |
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===Medical uses=== |
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It has been used to reverse hypertension caused by [[protamine]] (which in turn was administered to reverse the effects of [[heparin]] overdose).<ref name="pmid8969033">{{cite journal |author=van der Starre PJ, Solinas C |title=Ketanserin in the treatment of protamine-induced pulmonary hypertension |journal=Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital |volume=23 |issue=4 |pages=301–4 |year=1996 |pmid=8969033 |pmc=325377 |doi= |url=}}</ref> |
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Ketanserin is classified as an [[antihypertensive]] by the [[World Health Organization]]<ref>[http://www.whocc.no/atc_ddd_index/?code=C02KD01 ATC/DDD Index<!-- Bot generated title -->]</ref> and the [[National Institute of Health]].<ref>[https://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?mode=&term=Ketanserin Ketanserin<!-- Bot generated title -->]</ref> |
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It has been used to reverse pulmonary hypertension caused by [[protamine]] (which in turn was administered to reverse the effects of [[heparin]] overdose).<ref name="pmid8969033">{{cite journal | vauthors = van der Starre PJ, Solinas C | title = Ketanserin in the treatment of protamine-induced pulmonary hypertension | journal = Texas Heart Institute Journal | volume = 23 | issue = 4 | pages = 301–304 | year = 1996 | pmid = 8969033 | pmc = 325377 }}</ref> |
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The reduction in hypertension is not associated with reflex tachycardia.<ref name="pmid2786422">{{cite journal |author=Hodsman NB, Colvin JR, Kenny GN |title=Effect of ketanserin on sodium nitroprusside requirements, arterial pressure control and heart rate following coronary artery bypass surgery |journal=British journal of anaesthesia |volume=62 |issue=5 |pages=527–31 |year=1989 |month=May |pmid=2786422 |doi= 10.1093/bja/62.5.527|url=http://bja.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2786422}}</ref> |
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The reduction in hypertension is not associated with reflex tachycardia.<ref name="pmid2786422">{{cite journal | vauthors = Hodsman NB, Colvin JR, Kenny GN | title = Effect of ketanserin on sodium nitroprusside requirements, arterial pressure control and heart rate following coronary artery bypass surgery | journal = British Journal of Anaesthesia | volume = 62 | issue = 5 | pages = 527–531 | date = May 1989 | pmid = 2786422 | doi = 10.1093/bja/62.5.527 | doi-access = free }}</ref> |
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It has been used in cardiac surgery.<ref name="pmid19058975">{{cite journal | vauthors = Elbers PW, Ozdemir A, van Iterson M, van Dongen EP, Ince C | title = Microcirculatory Imaging in Cardiac Anesthesia: Ketanserin Reduces Blood Pressure But Not Perfused Capillary Density | journal = Journal of Cardiothoracic and Vascular Anesthesia | volume = 23 | issue = 1 | pages = 95–101 | date = February 2009 | pmid = 19058975 | doi = 10.1053/j.jvca.2008.09.013 }}</ref> |
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=== As a radioligand === |
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With [[tritium]] (<sup>3</sup>H) [[Radioactivity|radioactively]] labeled ketanserin is used as a [[radioligand]] for the serotonin 5-HT<sub>2A</sub> receptor, e.g. in [[receptor binding assay]]s and [[autoradiography]].<ref>{{Cite journal |
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| author = Simon B. Eickhoff, Axel Schleicher, Filip Scheperjans, Nicola Palomero-Gallagher & [[Karl Zilles]] |
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| title = Analysis of neurotransmitter receptor distribution patterns in the cerebral cortex |
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| journal = [[NeuroImage]] |
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| year = 2007 |
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| volume = 34 |
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| pages = 1317–1330 |
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| doi = 10.1016/j.neuroimage.2006.11.016 |
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| pmid = 17182260 |
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| issue = 4 |
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}}</ref> |
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This radiolabeling enables the study of the [[serotonin-2A receptor]] distribution in the [[human brain]].<ref>{{Cite journal |
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| author = A. Pazos, A. Probst, J. M. Palacios |
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| title = Serotonin receptors in the Human Brain—IV. Autoradiographic mapping of serotonin-2 receptors |
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| journal = [[Neuroscience (journal)|Neuroscience]] |
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| volume = 21 |
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| issue = 1 |
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| pages = 123–139 |
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| pmid = 3601071 |
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| doi = 10.1016/0306-4522(87)90327-7 |
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| year = 1987 |
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}}</ref> |
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A 2000 [[Cochrane Review]] found that, compared to placebo, ketanserin did not provide significant relief for people suffering from [[Raynaud's phenomenon]] attacks in the setting of [[progressive systemic sclerosis]] (an autoimmune disorder). While the frequency of the attacks was unaffected by ketanserin, there was a reduction in the duration of the individual attacks. However, due to the significant adverse effect burden, the authors concluded that ketanserin's utility for this indication is likely unbeneficial.<ref name="Pope Cochrane">{{cite journal | vauthors = Pope J, Fenlon D, Thompson A, Shea B, Furst D, Wells G, Silman A | title = Ketanserin for Raynaud's phenomenon in progressive systemic sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD000954 | date = 2000 | volume = 1998 | pmid = 10796396 | pmc = 7032891 | doi = 10.1002/14651858.CD000954 }}</ref> |
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An autoradiography study of the human [[cerebellum]] has found an increasing binding of H-3-ketanserin with [[aging|age]] (from below 50 [[Molarity|femtomol]] per milligram tissue at around 30 years og age to over 100 above 75 years).<ref>{{Cite journal |
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| author = Sharon L. Eastwood, Philip W. J. Burnet, Rebecca Gittins, Kate Baker, Paul J. Harrison |
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| title = Expression of serotonin 5-HT<sub>2A</sub> receptors in the human cerebellum and alterations in schizophrenia |
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| journal = [[Synapse (journal)|Synapse]] |
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| volume = 42 |
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| issue = 2 |
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| pages = 104–114 |
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| month = November |
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| year = 2001 |
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| doi = 10.1002/syn.1106 |
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| pmid = 11574947 |
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}}</ref> |
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The same research team found no significant correlation with age in their [[homogenate binding]] study. |
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Ketanserin is a selective 5-HT<sub>2A</sub> receptor antagonist that was initially developed as an anti-hypertensive medicine. However, now the drug is available as a [[Topical gels|topical gel]] formulation for treating wounds, burns, ulcers, and anal fissures. Its action is through the acceleration of epithelialization. |
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===Research uses=== |
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With [[tritium]] (<sup>3</sup>H) [[Radioactivity|radioactively]] labeled ketanserin is used as a [[radioligand]] for serotonin 5-HT<sub>2</sub> receptors, e.g. in [[ligand binding assay|receptor binding assay]]s and [[autoradiography]].<ref name="pmid17182260">{{cite journal | vauthors = Eickhoff SB, Schleicher A, Scheperjans F, Palomero-Gallagher N, Zilles K | title = Analysis of neurotransmitter receptor distribution patterns in the cerebral cortex | journal = NeuroImage | volume = 34 | issue = 4 | pages = 1317–1330 | date = February 2007 | pmid = 17182260 | doi = 10.1016/j.neuroimage.2006.11.016 | s2cid = 23363050 }}</ref> This radio-labeling has enabled the study of serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] [[gene expression|distribution]] in the [[human brain]].<ref name="pmid3601071">{{cite journal | vauthors = Pazos A, Probst A, Palacios JM | title = Serotonin receptors in the human brain--IV. Autoradiographic mapping of serotonin-2 receptors | journal = Neuroscience | volume = 21 | issue = 1 | pages = 123–139 | date = April 1987 | pmid = 3601071 | doi = 10.1016/0306-4522(87)90327-7 | s2cid = 23711420 }}</ref> |
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An autoradiography study of the human [[cerebellum]] has found an increasing binding of <sup>3</sup>H-ketanserin with [[aging|age]] (from below 50 [[Molarity|femtomol]] per milligram tissue at around 30 years of age to over 100 above 75 years).<ref name="pmid11574947">{{cite journal | vauthors = Eastwood SL, Burnet PW, Gittins R, Baker K, Harrison PJ | title = Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia | journal = Synapse | volume = 42 | issue = 2 | pages = 104–114 | date = November 2001 | pmid = 11574947 | doi = 10.1002/syn.1106 | s2cid = 40304220 }}</ref> The same research team found no significant correlation with age in their [[homogenization (biology)|homogenate]] binding study. |
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Ketanserin has also been used with [[carbon]] (<sup>11</sup>C) [[Radioactivity|radioactively]] labeled NNC112 in order to image cortical [[Dopamine receptor D1|D<sub>1</sub> receptors]] without contamination by 5-HT<sub>2</sub> receptors.<ref>{{cite journal | vauthors = Catafau AM, Searle GE, Bullich S, Gunn RN, Rabiner EA, Herance R, Radua J, Farre M, Laruelle M | display-authors = 6 | title = Imaging cortical dopamine D1 receptors using [11C]NNC112 and ketanserin blockade of the 5-HT 2A receptors | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 30 | issue = 5 | pages = 985–993 | date = May 2010 | pmid = 20029452 | pmc = 2949183 | doi = 10.1038/jcbfm.2009.269 }}</ref> |
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Increasing research into the use of [[psychedelic drug|psychedelics]] as [[antidepressant]]s has seen ketanserin used to both block the hallucinogenic experience, and to disentangle the specific cognitive effects of 5-HT<sub>2A</sub> activation.<ref>{{cite journal | vauthors = Quednow BB, Kometer M, Geyer MA, Vollenweider FX | title = Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers | journal = Neuropsychopharmacology | volume = 37 | issue = 3 | pages = 630–640 | date = February 2012 | pmid = 21956447 | pmc = 3260978 | doi = 10.1038/npp.2011.228 }}</ref> |
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==Pharmacology== |
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{| class="wikitable floatright" |
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|+ Human molecular targets of ketanserin<ref name="NIMH-PDSP">[https://pdsp.unc.edu/databases/pdsp.php NIMH Psychoactive Drug Screening Program]</ref><ref name="IUPHAR">{{cite web |url=https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=88 |title = Ketanserin Ligand page | work = IUPHAR/BPS Guide to PHARMACOLOGY }}</ref> |
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! Target |
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! Affinity (K<sub>i</sub>) |
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! Ref(s) |
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|- |
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| [[alpha-1A adrenergic receptor|α<sub>1A</sub>-adrenergic]] |
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| 6.3 nM |
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| <ref name="IUPHAR" /> |
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|- |
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| [[alpha-1B adrenergic receptor|α<sub>1B</sub>-adrenergic]] |
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| 6.3 nM |
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| <ref name="IUPHAR" /> |
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|- |
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| [[alpha-1D adrenergic receptor|α<sub>1D</sub>-adrenergic]] |
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| 16 nM |
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| <ref name="IUPHAR" /> |
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|- |
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| [[alpha-2A adrenergic receptor|α<sub>2A</sub>-adrenergic]] |
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| 372 nM (HT29) |
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| <ref name="NIMH-PDSP" /> |
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|- |
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| [[alpha-2B adrenergic receptor|α<sub>2B</sub>-adrenergic]] |
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| 199 nM |
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| <ref name="NIMH-PDSP" /> |
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|- |
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| [[alpha-2C adrenergic receptor|α<sub>2C</sub>-adrenergic]] |
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| 159 nM (opossum) |
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| <ref name="NIMH-PDSP" /> |
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|- |
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| [[5-HT1A receptor|5-HT<sub>1A</sub>]] |
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| 1,044–>10,000 nM |
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| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
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|- |
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| [[5-HT1B receptor|5-HT<sub>1B</sub>]] |
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| 2,515–6,300 nM |
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| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
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|- |
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| [[5-HT1D receptor|5-HT<sub>1D</sub>]] |
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| 32–>10,000 nM |
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| <ref name="IUPHAR" /><ref name="Meneses2014" /><ref name="OlivierWijngaarden1997">{{cite book| vauthors = Olivier B, van Wijngaarden I, Soudijn W |url= https://books.google.com/books?id=lfo0hGqIex0C&pg=PA118 |title=Serotonin Receptors and their Ligands|date=10 July 1997|publisher=Elsevier|isbn=978-0-08-054111-2|pages=118–}}</ref> |
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|- |
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| [[5-HT1E receptor|5-HT<sub>1E</sub>]] |
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| >10,000 nM |
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| <ref name="NIMH-PDSP" /> |
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|- |
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| [[5-HT1F receptor|5-HT<sub>1F</sub>]] |
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| 1.25–>10,000 nM |
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| <ref name="NIMH-PDSP" /> |
|||
|- |
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| [[5-HT2A receptor|5-HT<sub>2A</sub>]] |
|||
| 0.20–9.8 nM |
|||
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] |
|||
| 200–3,236 nM |
|||
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] |
|||
| 17–186 nM |
|||
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT3 receptor|5-HT<sub>3</sub>]] |
|||
| >10,000 nM (rodent) |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT4 receptor|5-HT<sub>4L</sub>]] |
|||
| 1,000 nM (rat) |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] |
|||
| 20,000 nM |
|||
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT5B receptor|5-HT<sub>5B</sub>]] |
|||
| 1,000–1,585 nM (rodent) |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT6 receptor|5-HT<sub>6</sub>]] |
|||
| 2,800 nM |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[5-HT7 receptor|5-HT<sub>7</sub>]] |
|||
| 320–1,334 nM |
|||
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[D1 receptor|D<sub>1</sub>]] |
|||
| 190–464 nM |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[D2 receptor|D<sub>2</sub>]] |
|||
| >10,000 nM |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[D3 receptor|D<sub>3</sub>]] |
|||
| ? |
|||
| |
|||
|- |
|||
| [[D4 receptor|D<sub>4</sub>]] |
|||
| 148 nM (canine) |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[D5 receptor|D<sub>5</sub>]] |
|||
| 2,500 nM |
|||
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[H1 receptor|H<sub>1</sub>]] |
|||
| 1.79 nM |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[Dopamine transporter|DAT]] |
|||
| >10,000 nM |
|||
| <ref name="NIMH-PDSP" /> |
|||
|- |
|||
| [[VMAT1]] |
|||
| 1,600 nM |
|||
| <ref name="IUPHAR" /> |
|||
|- |
|||
| [[VMAT2]] |
|||
| 500 nM |
|||
| <ref name="IUPHAR" /> |
|||
|} |
|||
===Pharmacodynamics=== |
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Ketanserin is a high-affinity non-selective [[receptor antagonist|antagonist]] of [[5-HT2 receptor|5-HT<sub>2</sub> receptors]] in rodents,<ref name="NIMH-PDSP" /><ref>{{cite journal | vauthors = Creed-Carson M, Oraha A, Nobrega JN | title = Effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats | journal = Behavioural Brain Research | volume = 219 | issue = 2 | pages = 273–279 | date = June 2011 | pmid = 21262266 | doi = 10.1016/j.bbr.2011.01.025 | s2cid = 205882443 }}</ref><ref name="Meneses2014">{{cite book| vauthors = Meneses A |title=The Role of 5-HT Systems on Memory and Dysfunctional Memory: Emergent Targets for Memory Formation and Memory Alterations|url=https://books.google.com/books?id=x_TJAgAAQBAJ&pg=PA23|date=11 March 2014|publisher=Elsevier Science|isbn=978-0-12-801083-9|pages=23–}}</ref> In addition to the 5-HT<sub>2</sub> receptors, ketanserin is also a high affinity antagonist for the [[H1 receptor|H<sub>1</sub> receptor]].<ref name="Coyne2008">{{cite book| vauthors = Coyne CP |title=Comparative Diagnostic Pharmacology: Clinical and Research Applications in Living-System Models|url=https://books.google.com/books?id=Kar-JGFMe-AC&pg=PA104|date=9 January 2008|publisher=John Wiley & Sons|isbn=978-0-470-34429-3|pages=104–}}</ref> It has also been found to block the [[vesicular monoamine transporter 2]] (VMAT2).<ref name="MullerJacobs2009">{{cite book| vauthors = Muller CP, Jacobs B |title=Handbook of the Behavioral Neurobiology of Serotonin|url=https://books.google.com/books?id=aomaKqIE1jUC&pg=PA592|date=30 December 2009|publisher=Academic Press|isbn=978-0-08-087817-1|pages=592–}}</ref><ref name="pmid9327887">{{cite book | vauthors = Henry JP, Sagné C, Botton D, Isambert MF, Gasnier B | title = Molecular Pharmacology of the Vesicular Monoamine Transporter | series = Advances in Pharmacology | location = San Diego, Calif. | volume = 42 | pages = 236–9 (237) | date = 1998 | pmid = 9327887 | doi = 10.1016/s1054-3589(08)60736-x | url = https://books.google.com/books?id=sNQ7IA3y2kAC&pg=PA237 |publisher=Academic Press|isbn=978-0-08-058134-7 }}</ref> |
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===Pharmacokinetics=== |
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The [[bioavailability]] of ketanserin is 50%.<ref name="Wolverton2007" /><ref name="SaitōMinami1992" /> The [[plasma protein binding]] of ketanserin is 95.0% and it is mainly bound to [[human serum albumin|albumin]].<ref name="SaitōMinami1992" /> The [[elimination half-life]] of ketanserin is 10 to 29 hours.<ref name="ColdDahl2013" /><ref name="Wolverton2007" /> |
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==Synthesis== |
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[[File:Ketanserin synthesis.svg|center|500px|thumb|[https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-11-0005 Thieme] Patents:<ref>{{cite patent | inventor = Vandenberk J, Kennis L, Van der Aa M, Van Heertum A | country = US | number = 4335127 | gdate = 1982 | assign1 = Janssen Pharmaceutica, N.V. }}</ref><ref>{{cite patent | inventor = Signorini R, Verga A | country = EP | number = 0098499 | gdate = 1984 | assign1 = Ravizza SpA }}</ref> Sino:<ref>{{cite patent | inventor = Shiwen R, et al. | country = CN | number = 106866625 | gdate = 2017 | assign1 = Shanghai Ding Ya Pharmaceutical Chemistry Science And Technology Ltd) }}</ref> Revised:<ref>{{cite journal | vauthors = Fakhraian H, Heydary M | title = Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5. HCl) via 3-(2-Chloroethyl)-2, 4-(1H, 3H)-quinazolinedione (2) or Dihydro-5H-oxazole (2, 3-b) quinazolin-5-one (1). | journal = Journal of Heterocyclic Chemistry | date = January 2014 | volume = 51 | issue = 1 | pages = 151–156 | doi = 10.1002/jhet.1897 }}.</ref> Analogues<ref name="pmid1479590">{{cite journal | vauthors = Herndon JL, Ismaiel A, Ingher SP, Teitler M, Glennon RA | title = Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding | journal = Journal of Medicinal Chemistry | volume = 35 | issue = 26 | pages = 4903–10 | date = December 1992 | pmid = 1479590 | doi = 10.1021/jm00104a017 }}</ref>]] |
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Either 3-(2-Chloroethyl)quinazoline-2,4(1H,3H)-dione [5081-87-8] ('''1a'''), or alternatively 2,3-dihydro-[1,3]oxazolo[2,3-b]quinazolin-5-one [52727-44-3] ('''1b''') can be used as starting material. Attachment of the sidechain to 4-(4-Fluorobenzoyl)piperidine [56346-57-7] ('''2''') completes synthesis synthesis of Ketanserin ('''3'''). |
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== See also == |
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* [[Altanserin]] |
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* [[Pirenperone]] |
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* [[Setoperone]] |
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* [[Pelanserin]] |
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{{clear}} |
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== References == |
== References == |
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{{Reflist |
{{Reflist}} |
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{{Antihypertensives |
{{Antihypertensives}} |
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{{Navboxes |
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{{Serotonergics}} |
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| title = [[Pharmacodynamics]] |
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| titlestyle = background:#ccccff |
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| list1 = |
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{{Adrenergic receptor modulators}} |
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{{Dopamine receptor modulators}} |
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{{Histamine receptor modulators}} |
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{{Monoamine reuptake inhibitors}} |
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{{Serotonin receptor modulators}} |
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}} |
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[[Category:5- |
[[Category:5-HT1D antagonists]] |
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[[Category: |
[[Category:5-HT2A antagonists]] |
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[[Category:5-HT2C antagonists]] |
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[[Category:5-HT6 antagonists]] |
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[[Category:5-HT7 antagonists]] |
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[[Category:Alpha-1 blockers]] |
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[[Category:Alpha-2 blockers]] |
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[[Category:Antihypertensive agents]] |
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[[Category:D1 antagonists]] |
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[[Category:D2 antagonists]] |
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[[Category:Fluoroarenes]] |
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[[Category:H1 receptor antagonists]] |
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[[Category:Imides]] |
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[[Category:Janssen Pharmaceutica]] |
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[[Category:Ketones]] |
[[Category:Ketones]] |
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[[Category:Piperidines]] |
[[Category:Piperidines]] |
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[[Category: |
[[Category:Quinazolinones]] |
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[[Category: |
[[Category:VMAT inhibitors]] |
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[[Category:Ureas]] |
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[[Category:Imides]] |
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[[de:Ketanserin]] |
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[[ja:ケタンセリン]] |
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[[pt:Cetanserina]] |