Ketanserin

Template:Short description Template:Cs1 config Template:Drugbox Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospastic disorders.<ref name="Symoens1990">Template:Cite journal</ref><ref name="BrogdenSorkin1990">Template:Cite journal</ref><ref name="PerssonHeykanksHedner1991">Template:Cite journal</ref> It is also used in scientific research as an antiserotonergic agent in the study of the serotonin system; specifically, the 5-HT₂ receptor family.<ref name="Ahuja2005">Template:Cite book</ref> The drug is taken by mouth.<ref name="BrogdenSorkin1990" /><ref name="PerssonHeykanksHedner1991" />

Side effects of ketanserin include dizziness, tiredness, edema, dry mouth, weight gain, and QT interval prolongation.<ref name="BrogdenSorkin1990" /> Ketanserin acts as a selective antagonist of the serotonin 5-HT_2A, α₁-adrenergic, and histamine H₁ receptors.<ref name="BrogdenSorkin1990" /><ref name="Awouters1985">Template:Cite journal</ref><ref name="CaseyCuiBooth2022">Template:Cite journal</ref> It also shows lower affinity for various other targets.<ref name="CaseyCuiBooth2022" />

Ketanserin was discovered at Janssen Pharmaceutica in 1980.<ref name="Healy2009">Template:Cite book</ref><ref name="Schwartz1989">Template:Cite book</ref> It was the first serotonin 5-HT_2A receptor antagonist to be discovered that showed selectivity over other serotonin receptors.<ref name="CaseyCuiBooth2022" /> The drug is not available in the United States<ref name="Wolverton2007" /> and is mostly no longer marketed throughout the rest of the world.<ref name="IndexNomininum2004" /><ref name="Drugs.com-International">Template:Cite web</ref>

Uses

Medical uses

Ketanserin is classified as an antihypertensive by the World Health Organization<ref>ATC/DDD Index</ref> and the National Institute of Health.<ref>Ketanserin</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">Template:Cite journal</ref>

The reduction in hypertension is not associated with reflex tachycardia.<ref name="pmid2786422">Template:Cite journal</ref>

It has been used in cardiac surgery.<ref name="pmid19058975">Template:Cite journal</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">Template:Cite journal</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 gel formulation for treating wounds, burns, ulcers, and anal fissures. Its action is through the acceleration of epithelialization.

Research uses

With tritium (³H) radioactively labeled ketanserin is used as a radioligand for serotonin 5-HT₂ receptors, e.g. in receptor binding assays and autoradiography.<ref name="pmid17182260">Template:Cite journal</ref> This radio-labeling has enabled the study of serotonin 5-HT_2A receptor distribution in the human brain.<ref name="pmid3601071">Template:Cite journal</ref>

An autoradiography study of the human cerebellum has found an increasing binding of ³H-ketanserin with age (from below 50 femtomol per milligram tissue at around 30 years of age to over 100 above 75 years).<ref name="pmid11574947">Template:Cite journal</ref> The same research team found no significant correlation with age in their homogenate binding study.

Ketanserin has also been used with carbon (¹¹C) radioactively labeled NNC112 in order to image cortical D₁ receptors without contamination by 5-HT₂ receptors.<ref>Template:Cite journal</ref>

Increasing research into the use of psychedelics as antidepressants has seen ketanserin used to both block the hallucinogenic experience, and to disentangle the specific cognitive effects of 5-HT_2A activation.<ref name="HalmanKongSarris2024">Template:Cite journal</ref> Ketanserin has been found to block the psychedelic effects of psilocybin,<ref name="VollenweiderVollenweider-ScherpenhuyzenBäbler1998">Template:Cite journal</ref> lysergic acid diethylamide (LSD),<ref name="HolzeVizeliLey2021">Template:Cite journal</ref><ref name="BeckerKlaiberHolze2023">Template:Cite journal</ref> mescaline,<ref name="KlaiberSchmidBecker2024">Template:Cite journal</ref> and ayahuasca (dimethyltryptamine)<ref name="ValleMaquedaRabella2016">Template:Cite journal</ref> in clinical studies.<ref name="HalmanKongSarris2024" /><ref name="HolzeSinghLiechti2024">Template:Cite journal</ref>

Pharmacology

Human molecular targets of ketanserin<ref name="NIMH-PDSP">NIMH Psychoactive Drug Screening Program</ref><ref name="IUPHAR">Template:Cite web</ref><ref name="CaseyCuiBooth2022" />

Target	Affinity (Ki)	Ref(s)
5-HT1A	1,044–>10,000 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
5-HT1B	2,515–6,300 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
5-HT1D	32–>10,000 nM	<ref name="IUPHAR" /><ref name="Meneses2014" /><ref name="OlivierWijngaarden1997">Template:Cite book</ref>
5-HT1E	>10,000 nM	<ref name="NIMH-PDSP" />
5-HT1F	1.25–>10,000 nM	<ref name="NIMH-PDSP" />
5-HT2A	0.20–9.8 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
5-HT2B	200–3,236 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
5-HT2C	17–186 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
5-HT3	>10,000 nM (rodent)	<ref name="NIMH-PDSP" />
5-HT4L	1,000 nM (rat)	<ref name="NIMH-PDSP" />
5-HT5A	20,000 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
5-HT5B	1,000–1,585 nM (rodent)	<ref name="NIMH-PDSP" />
5-HT6	2,800 nM	<ref name="NIMH-PDSP" />
5-HT7	320–1,334 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
D1	190–464 nM	<ref name="NIMH-PDSP" />
D2	>10,000 nM	<ref name="NIMH-PDSP" />
D3	?
D4	148 nM (canine)	<ref name="NIMH-PDSP" />
D5	2,500 nM	<ref name="IUPHAR" /><ref name="NIMH-PDSP" />
α1A	6.3 nM	<ref name="IUPHAR" />
α1B	6.3 nM	<ref name="IUPHAR" />
α1D	16 nM	<ref name="IUPHAR" />
α2A	372 nM (HT29)	<ref name="NIMH-PDSP" />
α2B	199 nM	<ref name="NIMH-PDSP" />
α2C	159 nM (opossum)	<ref name="NIMH-PDSP" />
H1	1.79 nM	<ref name="NIMH-PDSP" />
DAT	>10,000 nM	<ref name="NIMH-PDSP" />
VMAT1	1,600 nM	<ref name="IUPHAR" />
VMAT2	22–540 nM	<ref name="IUPHAR" /><ref name="CaseyCuiBooth2022" />

Pharmacodynamics

Ketanserin is a high-affinity non-selective antagonist of 5-HT₂ receptors in rodents.<ref name="NIMH-PDSP" /><ref>Template:Cite journal</ref><ref name="Meneses2014">Template:Cite book</ref><ref name="Glennon1987">Template:Cite journal</ref> In addition to the 5-HT₂ receptors, ketanserin is also a high affinity antagonist for the H₁ receptor.<ref name="Coyne2008">Template:Cite book</ref> It has also been found to block the vesicular monoamine transporter 2 (VMAT2).<ref name="MullerJacobs2009">Template:Cite book</ref><ref name="pmid9327887">Template:Cite book</ref>

Occupancy of the serotonin 5-HT_2A receptor by ketanserin in humans has been studied.<ref name="HolzeMadsenSvarer2024">Template:Cite journal</ref>

Pharmacokinetics

The bioavailability of ketanserin is 50%.<ref name="Wolverton2007" /><ref name="SaitōMinami1992" /> The drug's ability to cross the blood–brain barrier varies in different species, with higher permeability in humans, monkeys, and minipigs than in mice or rats.<ref name="KwanMantschMcCorvy2025">Template:Cite journal</ref> This is probably due to ketanserin being a P-glycoprotein substrate and due to varying capacity of P-glycoprotein in limiting blood–brain barrier penetration in different species.<ref name="KwanMantschMcCorvy2025" /> The plasma protein binding of ketanserin is 95.0% and it is mainly bound to albumin.<ref name="SaitōMinami1992" /> The elimination half-life of ketanserin is 10 to 29Template:Nbsphours.<ref name="ColdDahl2013" /><ref name="Wolverton2007" />

Chemistry

Ketanserin is a piperidinylethylquinazoline derivative.<ref name="Elks2014" /><ref name="MortonHall2012" />

Synthesis

Thieme Patents:<ref>Template:Cite patent</ref><ref>Template:Cite patent</ref> Sino:<ref>Template:Cite patent</ref> Revised:<ref>Template:Cite journal.</ref> Analogues<ref name="pmid1479590">Template:Cite journal</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 the synthesis of Ketanserin (3).

Analogues

Analogues of ketanserin include altanserin, ocaperidone, paliperidone, pelanserin, pirenperone, risperidone, ritanserin, and setoperone, among others.<ref name="Elks2014" /><ref name="IndexNomininum2004" />

History

Ketanserin was first described in the scientific literature by 1980.<ref name="Elks2014" /><ref name="scholar_10067446726966900160">De Clerck F (1979) The effect of oral administration of R41468 to human volunteers on the ex vivo platelet aggregation induced or potentiated by serotonin. Clinical Research Report on R41468 No. 11. Janssen Pharmaceutica, Beerse, Belgium. https://scholar.google.com/scholar?cluster=10067446726966900160</ref><ref name="JanssenPharmaceutica">Janssen Pharmaceutica. (1980). R 41 468: The first pure and selective serotonin S2 (5-HT2) receptor blocking agent. Investigational New Drug Brochure. https://scholar.google.com/scholar?cluster=3284059525459562521</ref><ref name="VanNuetenJanssenVanBeek1981">Template:Cite journal</ref>

Society and culture

Names

Ketanserin is the generic name of the drug and its Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink.<ref name="IndexNomininum2004">Template:Cite book</ref><ref name="MortonHall2012">Template:Cite book</ref><ref name="Elks2014">Template:Cite book</ref> It is also known by its major brand names Sufrexal and Serefrex and by its former developmental code names R-41468, KJK-945, and R-49945.<ref name="IndexNomininum2004" /><ref name="MortonHall2012" /><ref name="Elks2014" />

External links

• How To Stop A Psychedelic Trip: The Promise of Ketanserin - Psychedelic Science Review (PSR)