Ketanserin: Difference between revisions

{{Short description|Antihypertensive agent}}

{{cs1 config|name-list-style=vanc}}

{{Drugbox

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 420466712

| IUPAC_name = 3-<nowiki/>{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1''H'',3''H'')-dione

| image = Ketanserin.png

| width = 250px

| image2 = Ketanserin_3D.png

| 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 = [[Oral administration|Oral]]

<!--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 = 95.0% (mainly [[human serum albumin|albumin]]<ref name="SaitōMinami1992" />

| metabolism =

| 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 =

<!--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

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D02363

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 6123

| synonyms = R41468; R-41468; R-41,468

<!--Chemical data-->

| C=22 | H=22 | F=1 | N=3 | O=3

| SMILES = c1ccc2c(c1)c(=O)n(c(=O)[nH]2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F

'''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-HT₂ 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" />

===Medical uses===

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>

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>

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 | 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 [[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>

Ketanserin is a selective 5-HT_2A 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.

===Research uses===

With [[tritium]] (³H) [[Radioactivity|radioactively]] labeled ketanserin is used as a [[radioligand]] for serotonin 5-HT₂ 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_2A 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>

An autoradiography study of the human [[cerebellum]] has found an increasing binding of ³H-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.

Ketanserin has also been used with [[carbon]] (¹¹C) [[Radioactivity|radioactively]] labeled NNC112 in order to image cortical [[Dopamine receptor D1|D₁ receptors]] without contamination by 5-HT₂ 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>

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_2A 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>

==Pharmacology==

{| class="wikitable floatright"

|+ 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>

! Target

! Affinity (K_i)

! Ref(s)

|-

| [[alpha-1A adrenergic receptor|α_1A-adrenergic]]

| 6.3 nM

| <ref name="IUPHAR" />

|-

| [[alpha-1B adrenergic receptor|α_1B-adrenergic]]

| 6.3 nM

| <ref name="IUPHAR" />

|-

| [[alpha-1D adrenergic receptor|α_1D-adrenergic]]

| 16 nM

| <ref name="IUPHAR" />

|-

| [[alpha-2A adrenergic receptor|α_2A-adrenergic]]

| 372 nM (HT29)

| <ref name="NIMH-PDSP" />

|-

| [[alpha-2B adrenergic receptor|α_2B-adrenergic]]

| 199 nM

| <ref name="NIMH-PDSP" />

|-

| [[alpha-2C adrenergic receptor|α_2C-adrenergic]]

| 159 nM (opossum)

| <ref name="NIMH-PDSP" />

|-

| [[5-HT1A receptor|5-HT_1A]]

| 1,044–>10,000 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[5-HT1B receptor|5-HT_1B]]

| 2,515–6,300 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[5-HT1D receptor|5-HT_1D]]

| 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>

|-

| [[5-HT1E receptor|5-HT_1E]]

| >10,000 nM

| <ref name="NIMH-PDSP" />

|-

| [[5-HT1F receptor|5-HT_1F]]

| 1.25–>10,000 nM

| <ref name="NIMH-PDSP" />

|-

| [[5-HT2A receptor|5-HT_2A]]

| 0.20–9.8 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[5-HT2B receptor|5-HT_2B]]

| 200–3,236 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[5-HT2C receptor|5-HT_2C]]

| 17–186 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[5-HT3 receptor|5-HT₃]]

| >10,000 nM (rodent)

| <ref name="NIMH-PDSP" />

|-

| [[5-HT4 receptor|5-HT_4L]]

| 1,000 nM (rat)

| <ref name="NIMH-PDSP" />

|-

| [[5-HT5A receptor|5-HT_5A]]

| 20,000 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[5-HT5B receptor|5-HT_5B]]

| 1,000–1,585 nM (rodent)

| <ref name="NIMH-PDSP" />

|-

| [[5-HT6 receptor|5-HT₆]]

| 2,800 nM

| <ref name="NIMH-PDSP" />

|-

| [[5-HT7 receptor|5-HT₇]]

| 320–1,334 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[D1 receptor|D₁]]

| 190–464 nM

| <ref name="NIMH-PDSP" />

|-

| [[D2 receptor|D₂]]

| >10,000 nM

| <ref name="NIMH-PDSP" />

|-

| [[D3 receptor|D₃]]

| ?

|

|-

| [[D4 receptor|D₄]]

| 148 nM (canine)

| <ref name="NIMH-PDSP" />

|-

| [[D5 receptor|D₅]]

| 2,500 nM

| <ref name="IUPHAR" /><ref name="NIMH-PDSP" />

|-

| [[H1 receptor|H₁]]

| 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===

Ketanserin is a high-affinity non-selective [[receptor antagonist|antagonist]] of [[5-HT2 receptor|5-HT₂ 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-HT₂ receptors, ketanserin is also a high affinity antagonist for the [[H1 receptor|H₁ 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>

===Pharmacokinetics===

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&nbsp;hours.<ref name="ColdDahl2013" /><ref name="Wolverton2007" />

==Synthesis==

[[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>]]

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''').

== See also ==

* [[Altanserin]]

* [[Pirenperone]]

* [[Setoperone]]

* [[Pelanserin]]

{{clear}}

{{Reflist}}

{{Antihypertensives}}

{{Navboxes

| title = [[Pharmacodynamics]]

| titlestyle = background:#ccccff

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[[Category:5-HT1D antagonists]]

[[Category:5-HT2A antagonists]]

[[Category:5-HT2C antagonists]]

[[Category:5-HT6 antagonists]]

[[Category:5-HT7 antagonists]]

[[Category:Alpha-1 blockers]]

[[Category:Alpha-2 blockers]]

[[Category:Antihypertensive agents]]

[[Category:D1 antagonists]]

[[Category:D2 antagonists]]

[[Category:Fluoroarenes]]

[[Category:H1 receptor antagonists]]

[[Category:Imides]]

[[Category:Janssen Pharmaceutica]]

[[Category:Quinazolinones]]

[[Category:VMAT inhibitors]]