| Revision as of 10:20, 24 March 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{drugbox}} (no changed fields - added verified revid) per Chem/Drugbox validation (report errors or bugs)← Previous edit |
Latest revision as of 03:53, 14 January 2025 edit undoArthurfragoso (talk | contribs)Extended confirmed users, Template editors4,591 edits dark mode fix |
| (144 intermediate revisions by 72 users not shown) |
| Line 1: |
Line 1: |
|
|
{{Short description|Antihypertensive agent}} |
|
{{drugbox |
|
|
|
{{cs1 config|name-list-style=vanc}} |
|
| verifiedrevid = 414566780 |
|
|
|
{{Drugbox |
|
| IUPAC_name = 3-{2-ethyl}quinazoline-2,4(1''H'',3''H'')-dione |
|
|
|
| Verifiedfields = verified |
|
| image = Ketanserin.png |
|
|
|
| Watchedfields = verified |
|
| CASNo_Ref = {{cascite|correct|CAS}} |
|
|
|
| verifiedrevid = 420466712 |
|
|
| IUPAC_name = 3-<nowiki/>{2-ethyl}quinazoline-2,4(1''H'',3''H'')-dione |
|
|
| image = Ketanserin.png |
|
|
| image_class = skin-invert-image |
|
|
| width = 250px |
|
|
| image2 = Ketanserin_3D.png |
|
|
| image_class2 = bg-transparent |
|
|
| width2 = 235px |
|
|
|
|
|
<!--Clinical data--> |
|
|
| tradename = Sufrexal |
|
|
| Drugs.com = {{drugs.com|international|ketanserin}} |
|
|
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
|
|
| pregnancy_US = <!-- A / B / C / D / X --> |
|
|
| pregnancy_category = |
|
|
| legal_status = Rx-only |
|
|
| routes_of_administration = ] |
|
|
|
|
|
<!--Pharmacokinetic data--> |
|
|
| 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" /> |
|
|
| protein_bound = 95% (mainly ]<ref name="SaitōMinami1992" /><ref name="PerssonHeykanksHedner1991" /> |
|
|
| metabolism = Extensive<ref name="PerssonHeykanksHedner1991" /> |
|
|
| metabolites = • Ketanserin-ol<ref name="PerssonHeykanksHedner1991" /> |
|
|
| 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> |
|
|
| excretion = ]; 2% unchanged<ref name="PerssonHeykanksHedner1991" /> |
|
|
|
|
|
<!--Identifiers--> |
|
|
| CAS_number_Ref = {{cascite|correct|??}} |
|
|
| CAS_number = 74050-98-9 |
|
|
| ATC_prefix = C02 |
|
|
| ATC_suffix = KD01 |
|
|
| ATC_supplemental = {{ATCvet|D03|AX90}} |
|
|
| PubChem = 3822 |
|
|
| IUPHAR_ligand = 88 |
|
|
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
|
|
| DrugBank = DB12465 |
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
| ChemSpiderID = 3690 |
|
| ChemSpiderID = 3690 |
|
| UNII_Ref = {{fdacite|correct|FDA}} |
|
| UNII_Ref = {{fdacite|correct|FDA}} |
|
| UNII = 97F9DE4CT4 |
|
| UNII = 97F9DE4CT4 |
|
|
| KEGG_Ref = {{keggcite|correct|kegg}} |
|
| 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) |
|
|
|
| KEGG = D02363 |
|
| InChIKey = FPCCSQOGAWCVBH-UHFFFAOYAA |
|
|
|
| ChEBI_Ref = {{ebicite|correct|EBI}} |
|
| smiles = c1ccc2c(c1)c(=O)n(c(=O)2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F |
|
|
|
| ChEBI = 6123 |
|
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
|
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
|
| ChEMBL = 51 |
|
| ChEMBL = 51 |
|
|
| synonyms = R-41468; R41468; R-41,468; KJK-945; R-49945; R49945 |
|
|
|
|
|
<!--Chemical data--> |
|
|
| C=22 | H=22 | F=1 | N=3 | O=3 |
|
|
| SMILES = c1ccc2c(c1)c(=O)n(c(=O)2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F |
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
| 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) |
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChIKey = FPCCSQOGAWCVBH-UHFFFAOYSA-N |
|
| StdInChIKey = FPCCSQOGAWCVBH-UHFFFAOYSA-N |
|
| CAS_number = 74050-98-9 |
|
|
| ATC_prefix = C02 |
|
|
| ATC_suffix = KD01 |
|
|
| ATC_supplemental = {{ATCvet|D03|AX90}} |
|
|
| PubChem = 3822 |
|
|
| IUPHAR_ligand = 197 |
|
|
| IUPHAR_ligand = 88 |
|
|
| DrugBank = |
|
|
| KEGG_Ref = {{keggcite|correct|kegg}} |
|
|
| KEGG = D02363 |
|
|
| chemical_formula = |
|
|
| C=22|H=22|F=1|N=3|O=3 |
|
|
| molecular_weight = 395.43 g/mol |
|
|
| bioavailability = |
|
|
| protein_bound = |
|
|
| metabolism = |
|
|
| elimination_half-life = |
|
|
| excretion = |
|
|
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
|
|
| pregnancy_US = <!-- A / B / C / D / X --> |
|
|
| pregnancy_category= |
|
|
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
|
|
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
|
|
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
|
|
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
|
|
| legal_status = |
|
|
| routes_of_administration = |
|
|
}} |
|
}} |
|
|
<!-- Definition and medical uses --> |
|
'''Ketanserin''' is a drug with affinity for multiple G protein-coupled receptors (]). Initially it was believed to be a highly selective antagonist for serotonin ] receptors, however this is not true. Ketanserin only has good selectivity for ] receptors over ] receptors (~20-30 fold). Ketanserin also has high affinity for ] receptors, and very high affinity for ] |
|
|
|
'''Ketanserin''', sold under the brand name '''Sufrexal''', is an ] which is used to treat ] and ]s.<ref name="Symoens1990">{{cite journal | vauthors = Symoens J | title = Ketanserin: a novel cardiovascular drug | journal = Blood Coagul Fibrinolysis | volume = 1 | issue = 2 | pages = 219–224 | date = June 1990 | pmid = 2130934 | doi = | url = }}</ref><ref name="BrogdenSorkin1990">{{cite journal | vauthors = Brogden RN, Sorkin EM | title = Ketanserin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease | journal = Drugs | volume = 40 | issue = 6 | pages = 903–949 | date = December 1990 | pmid = 2079001 | doi = 10.2165/00003495-199040060-00010 | url = }}</ref><ref name="PerssonHeykanksHedner1991">{{cite journal | vauthors = Persson B, Heykants J, Hedner T | title = Clinical pharmacokinetics of ketanserin | journal = Clin Pharmacokinet | volume = 20 | issue = 4 | pages = 263–279 | date = April 1991 | pmid = 2036747 | doi = 10.2165/00003088-199120040-00002 | url = }}</ref> It is also used in ] as an ] ] in the study of the ] system; specifically, the ].<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> The drug is taken ].<ref name="BrogdenSorkin1990" /><ref name="PerssonHeykanksHedner1991" /> |
|
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 ] (~200 nM) and ] (~300 nM) receptors as well as weak affinity for dopamine ] and ] 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></ref>) |
|
|
|
|
|
|
|
<!-- Side effects and mechanism of action --> |
|
Receptors for which ketanserin has high affinity binding: |
|
|
|
]s of ketanserin include ], ], ], ], ], and ].<ref name="BrogdenSorkin1990" /> Ketanserin acts as a ] ] of the ] ], ], and ] ]s.<ref name="BrogdenSorkin1990" /><ref name="Awouters1985">{{cite journal | last=Awouters | first=Frans | title=The pharmacology of ketanserin, the first selective serotonin S<sub>2</sub>‐antagonist | journal=Drug Development Research | publisher=Wiley | volume=6 | issue=4 | year=1985 | issn=0272-4391 | doi=10.1002/ddr.430060402 | pages=263–300}}</ref><ref name="CaseyCuiBooth2022">{{cite journal | vauthors = Casey AB, Cui M, Booth RG, Canal CE | title = "Selective" serotonin 5-HT2A receptor antagonists | journal = Biochem Pharmacol | volume = 200 | issue = | pages = 115028 | date = June 2022 | pmid = 35381208 | pmc = 9252399 | doi = 10.1016/j.bcp.2022.115028 | url = | quote = Since its discovery by Janssen Pharmaceuticals in 1981 (35), the quinazoline derivative ketanserin is among the most widely used tools for probing 5-HT2AR function in preclinical research (26–28, 36), and the sole antagonist used to delineate the 5-HT2AR-dependent effects of serotonergic psychedelics in humans (37–41). Although ketanserin was the first 5-HT2AR antagonist discovered that lacks high affinity for other serotonin and dopamine receptors, it is less appreciated that it has high affinity at several aminergic receptors, including α1A-, α1B-, α1D-adrenergic, and histamine H1 receptors (35, 42–44), as well as, moderate affinity at α2B-adrenergic and 5-HT2C receptors (Table 1). These off-target activities limit the utility of ketanserin as a specific tool for assessing 5-HT2AR activity.}}</ref> It also shows lower ] for various other ]s.<ref name="CaseyCuiBooth2022" /> |
|
*5-HT<sub>2A</sub> = 2-3 nM (rat and human) |
|
|
*5-HT<sub>2C</sub> = 50 nM (rat), 100 nM (human) |
|
|
*alpha-1 adrenergic = ~40 nM |
|
|
*Histamine H1 = 2 nM |
|
|
|
|
|
|
|
<!-- History, society, and culture --> |
|
Ketanserin was discovered at ] in 1980. |
|
|
|
Ketanserin was discovered at ] 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=}}</ref> It was the first serotonin 5-HT<sub>2A</sub> receptor antagonist to be discovered that showed selectivity over other serotonin receptors.<ref name="CaseyCuiBooth2022" /> The drug is not available in the ]<ref name="Wolverton2007" /> and is mostly no longer marketed throughout the rest of the world.<ref name="IndexNomininum2004" /><ref name="Drugs.com-International">{{cite web | title=Ketanserin (International database) | website=Drugs.com | date=6 October 2024 | url=https://www.drugs.com/international/ketanserin.html | access-date=8 October 2024}}</ref> |
|
|
|
|
|
==Uses== |
|
==Uses== |
|
===Antihypertensive=== |
|
===Medical uses=== |
|
It is classified as an ] by the ]<ref></ref> and the ].<ref></ref> |
|
Ketanserin is classified as an ] by the ]<ref></ref> and the ].<ref></ref> |
|
|
|
|
|
It has been used to reverse hypertension caused by ] (which in turn was administered to reverse the effects of ] 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> |
|
It has been used to reverse pulmonary hypertension caused by ] (which in turn was administered to reverse the effects of ] 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> |
|
|
|
|
|
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> |
|
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> |
|
|
|
|
|
It has been used in cardiac surgery.<ref name="pmid19058975">{{cite journal |author=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=J. Cardiothorac. Vasc. Anesth. |volume= 23|issue= 1|pages= 95|year=2008 |month=December |pmid=19058975 |doi=10.1053/j.jvca.2008.09.013 |url=http://linkinghub.elsevier.com/retrieve/pii/S1053-0770(08)00294-2}}</ref> |
|
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> |
|
|
|
|
|
|
A 2000 ] found that, compared to placebo, ketanserin did not provide significant relief for people suffering from ] attacks in the setting of ] (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> |
|
=== As a radioligand === |
|
|
With ] (<sup>3</sup>H) ] labeled ketanserin is used as a ] for the serotonin 5-HT<sub>2A</sub> receptor, e.g. in ]s and ].<ref>{{Cite journal |
|
|
| author = Simon B. Eickhoff, Axel Schleicher, Filip Scheperjans, Nicola Palomero-Gallagher & ] |
|
|
| title = Analysis of neurotransmitter receptor distribution patterns in the cerebral cortex |
|
|
| journal = ] |
|
|
| year = 2007 |
|
|
| volume = 34 |
|
|
| pages = 1317–1330 |
|
|
| doi = 10.1016/j.neuroimage.2006.11.016 |
|
|
| pmid = 17182260 |
|
|
| issue = 4 |
|
|
}}</ref> |
|
|
This radiolabeling enables the study of the ] distribution in the ].<ref>{{Cite journal |
|
|
| author = A. Pazos, A. Probst, J. M. Palacios |
|
|
| title = Serotonin receptors in the Human Brain—IV. Autoradiographic mapping of serotonin-2 receptors |
|
|
| journal = ] |
|
|
| volume = 21 |
|
|
| issue = 1 |
|
|
| pages = 123–139 |
|
|
| pmid = 3601071 |
|
|
| doi = 10.1016/0306-4522(87)90327-7 |
|
|
| year = 1987 |
|
|
}}</ref> |
|
|
|
|
|
|
|
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 ] formulation for treating wounds, burns, ulcers, and anal fissures. Its action is through the acceleration of epithelialization. |
|
An autoradiography study of the human ] has found an increasing binding of H-3-ketanserin with ] (from below 50 ] per milligram tissue at around 30 years og age to over 100 above 75 years).<ref>{{Cite journal |
|
|
| author = Sharon L. Eastwood, Philip W. J. Burnet, Rebecca Gittins, Kate Baker, Paul J. Harrison |
|
|
| title = Expression of serotonin 5-HT<sub>2A</sub> receptors in the human cerebellum and alterations in schizophrenia |
|
|
| journal = ] |
|
|
| volume = 42 |
|
|
| issue = 2 |
|
|
| pages = 104–114 |
|
|
| month = November |
|
|
| year = 2001 |
|
|
| doi = 10.1002/syn.1106 |
|
|
| pmid = 11574947 |
|
|
}}</ref> |
|
|
The same research team found no significant correlation with age in their ] study. |
|
|
|
|
|
|
|
===Research uses=== |
|
== References == |
|
|
|
With ] (<sup>3</sup>H) ] labeled ketanserin is used as a ] for serotonin 5-HT<sub>2</sub> receptors, e.g. in ]s and ].<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 ] ] in the ].<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> |
|
{{Reflist|2}} |
|
|
|
|
|
|
|
An autoradiography study of the human ] has found an increasing binding of <sup>3</sup>H-ketanserin with ] (from below 50 ] 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 ] binding study. |
|
{{Antihypertensives and diuretics}} |
|
|
{{Serotonergics}} |
|
|
|
|
|
|
|
Ketanserin has also been used with ] (<sup>11</sup>C) ] labeled NNC112 in order to image cortical ] 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 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> |
|
] |
|
|
|
|
|
] |
|
|
|
Increasing research into the use of ] as ]s has seen ketanserin used to both ], and to disentangle the specific cognitive effects of 5-HT<sub>2A</sub> activation.<ref name="HalmanKongSarris2024">{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}</ref> Ketanserin has been found to block the psychedelic effects of ],<ref name="VollenweiderVollenweider-ScherpenhuyzenBäbler1998">{{cite journal | vauthors = Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D | title = Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action | journal = NeuroReport | volume = 9 | issue = 17 | pages = 3897–3902 | date = December 1998 | pmid = 9875725 | doi = 10.1097/00001756-199812010-00024 | url = }}</ref> ] (LSD),<ref name="HolzeVizeliLey2021">{{cite journal | vauthors = Holze F, Vizeli P, Ley L, Müller F, Dolder P, Stocker M, Duthaler U, Varghese N, Eckert A, Borgwardt S, Liechti ME | title = Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects | journal = Neuropsychopharmacology | volume = 46 | issue = 3 | pages = 537–544 | date = February 2021 | pmid = 33059356 | pmc = 8027607 | doi = 10.1038/s41386-020-00883-6 | url = }}</ref><ref name="BeckerKlaiberHolze2023">{{cite journal | vauthors = Becker AM, Klaiber A, Holze F, Istampoulouoglou I, Duthaler U, Varghese N, Eckert A, Liechti ME | title = Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants | journal = Int J Neuropsychopharmacol | volume = 26 | issue = 2 | pages = 97–106 | date = February 2023 | pmid = | pmc = 9926053 | doi = 10.1093/ijnp/pyac075 | url = }}</ref> ],<ref name="KlaiberSchmidBecker2024">{{cite journal | vauthors = Klaiber A, Schmid Y, Becker AM, Straumann I, Erne L, Jelusic A, Thomann J, Luethi D, Liechti ME | title = Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects | journal = Transl Psychiatry | volume = 14 | issue = 1 | pages = 395 | date = September 2024 | pmid = 39349427 | pmc = 11442856 | doi = 10.1038/s41398-024-03116-2 | url = }}</ref> and ] (])<ref name="ValleMaquedaRabella2016">{{cite journal | vauthors = Valle M, Maqueda AE, Rabella M, Rodríguez-Pujadas A, Antonijoan RM, Romero S, Alonso JF, Mañanas MÀ, Barker S, Friedlander P, Feilding A, Riba J | title = Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans | journal = Eur Neuropsychopharmacol | volume = 26 | issue = 7 | pages = 1161–1175 | date = July 2016 | pmid = 27039035 | doi = 10.1016/j.euroneuro.2016.03.012 | url = | hdl = 2117/101863 | hdl-access = free }}</ref> in clinical studies.<ref name="HalmanKongSarris2024" /><ref name="HolzeSinghLiechti2024">{{cite journal | vauthors = Holze F, Singh N, Liechti ME, D'Souza DC | title = Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile | journal = Biol Psychiatry Cogn Neurosci Neuroimaging | volume = 9 | issue = 5 | pages = 472–489 | date = May 2024 | pmid = | doi = 10.1016/j.bpsc.2024.01.007 | url = | doi-access = free }}</ref> |
|
|
|
|
|
==Pharmacology== |
|
|
{| class="wikitable floatright" |
|
|
|+ Human molecular targets of ketanserin<ref name="NIMH-PDSP"></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><ref name="CaseyCuiBooth2022" /> |
|
|
! Target |
|
|
! Affinity (K<sub>i</sub>) |
|
|
! Ref(s) |
|
|
|- |
|
|
| ] |
|
|
| 6.3 nM |
|
|
| <ref name="IUPHAR" /> |
|
|
|- |
|
|
| ] |
|
|
| 6.3 nM |
|
|
| <ref name="IUPHAR" /> |
|
|
|- |
|
|
| ] |
|
|
| 16 nM |
|
|
| <ref name="IUPHAR" /> |
|
|
|- |
|
|
| ] |
|
|
| 372 nM (HT29) |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 199 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 159 nM (opossum) |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 1,044–>10,000 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 2,515–6,300 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 32–>10,000 nM |
|
|
| <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> |
|
|
|- |
|
|
| ] |
|
|
| >10,000 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 1.25–>10,000 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 0.20–9.8 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 200–3,236 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 17–186 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| >10,000 nM (rodent) |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 1,000 nM (rat) |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 20,000 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 1,000–1,585 nM (rodent) |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 2,800 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 320–1,334 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 190–464 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| >10,000 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| ? |
|
|
| |
|
|
|- |
|
|
| ] |
|
|
| 148 nM (canine) |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 2,500 nM |
|
|
| <ref name="IUPHAR" /><ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 1.79 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| >10,000 nM |
|
|
| <ref name="NIMH-PDSP" /> |
|
|
|- |
|
|
| ] |
|
|
| 1,600 nM |
|
|
| <ref name="IUPHAR" /> |
|
|
|- |
|
|
| ] |
|
|
| 22–540 nM |
|
|
| <ref name="IUPHAR" /><ref name="CaseyCuiBooth2022" /> |
|
|
|} |
|
|
|
|
|
===Pharmacodynamics=== |
|
|
Ketanserin is a high-affinity non-selective ] of ] 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 ].<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 ] (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> |
|
|
|
|
|
] of the serotonin 5-HT<sub>2A</sub> receptor by ketanserin in humans has been studied.<ref name="HolzeMadsenSvarer2024">{{cite journal | vauthors = Holze F, Madsen MK, Svarer C, Gillings N, Stenbaek DS, Rudin D, Duthaler U, Liechti ME, Fisher PM, Knudsen GM | title = Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research | journal = Eur Neuropsychopharmacol | volume = 88 | issue = | pages = 43–48 | date = August 2024 | pmid = | doi = 10.1016/j.euroneuro.2024.07.003 | url = }}</ref> |
|
|
|
|
|
===Pharmacokinetics=== |
|
|
The ] of ketanserin is 50%.<ref name="Wolverton2007" /><ref name="SaitōMinami1992" /> The ] of ketanserin is 95.0% and it is mainly bound to ].<ref name="SaitōMinami1992" /> The ] of ketanserin is 10 to 29{{nbsp}}hours.<ref name="ColdDahl2013" /><ref name="Wolverton2007" /> |
|
|
|
|
|
==Chemistry== |
|
|
===Synthesis=== |
|
|
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>]] |
|
|
|
|
|
Either 3-(2-Chloroethyl)quinazoline-2,4(1H,3H)-dione ('''1a'''), or alternatively 2,3-dihydro-oxazoloquinazolin-5-one ('''1b''') can be used as starting material. Attachment of the sidechain to 4-(4-Fluorobenzoyl)piperidine ('''2''') completes the synthesis of Ketanserin ('''3'''). |
|
|
|
|
|
==Society and culture== |
|
|
===Names=== |
|
|
''Ketanserin'' is the ] of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|USAN|United States Adopted Name}}, {{Abbrlink|BAN|British Approved Name}}.<ref name="IndexNomininum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | series=Index Nominum: International Drug Directory | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA676 | access-date=8 October 2024 | page=676}}</ref> It is also known by its major brand name ''Sufrexal'' and by its former developmental code names ''R-41468'', ''KJK-945'', and ''R-49945''.<ref name="IndexNomininum2004" /> |
|
|
|
|
|
==See also== |
|
|
* ] |
|
|
* ] |
|
|
* ] |
|
|
* ] |
|
|
|
|
|
==References== |
|
|
{{Reflist}} |
|
|
|
|
|
{{Antihypertensives}} |
|
|
{{Navboxes |
|
|
| title = ] |
|
|
| titlestyle = background:#ccccff |
|
|
| list1 = |
|
|
{{Adrenergic receptor modulators}} |
|
|
{{Dopamine receptor modulators}} |
|
|
{{Histamine receptor modulators}} |
|
|
{{Monoamine reuptake inhibitors}} |
|
|
{{Serotonin receptor modulators}} |
|
|
}} |
|
|
|
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
|
|
|
|
] |
|
|
] |
|
|
] |
|