Chemistry:Ketanserin

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Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospastic disorders.[1][2][3] It is also used in scientific research as an antiserotonergic agent in the study of the serotonin system; specifically, the 5-HT2 receptor family.[4] The drug is taken orally.[2][3]

Side effects of ketanserin include dizziness, tiredness, edema, dry mouth, weight gain, and QT interval prolongation.[2] Ketanserin acts as a selective antagonist of the serotonin 5-HT2A, α1-adrenergic, and histamine H1 receptors.[2][5][6] It also shows lower affinity for various other targets.[6]

Ketanserin was discovered at Janssen Pharmaceutica in 1980.[7][8] It was the first serotonin 5-HT2A receptor antagonist to be discovered that showed selectivity over other serotonin receptors.[6] The drug is not available in the United States[9] and is mostly no longer marketed throughout the rest of the world.[10][11]

Uses

Medical uses

Ketanserin is classified as an antihypertensive by the World Health Organization[12] and the National Institute of Health.[13]

It has been used to reverse pulmonary hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose).[14]

The reduction in hypertension is not associated with reflex tachycardia.[15]

It has been used in cardiac surgery.[16]

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.[17]

Ketanserin is a selective 5-HT2A 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.[18] This radio-labeling has enabled the study of serotonin 5-HT2A receptor distribution in the human brain.[19]

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).[20] 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.[21]

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-HT2A activation.[22] Ketanserin has been found to block the psychedelic effects of psilocybin,[23] lysergic acid diethylamide (LSD),[24][25] mescaline,[26] and ayahuasca (dimethyltryptamine)[27] in clinical studies.[22][28]

Pharmacology

Human molecular targets of ketanserin[29][30][6]
Target Affinity (Ki) Ref(s)
5-HT1A 1,044–>10,000 nM [30][29]
5-HT1B 2,515–6,300 nM [30][29]
5-HT1D 32–>10,000 nM [30][31][32]
5-HT1E >10,000 nM [29]
5-HT1F 1.25–>10,000 nM [29]
5-HT2A 0.20–9.8 nM [30][29]
5-HT2B 200–3,236 nM [30][29]
5-HT2C 17–186 nM [30][29]
5-HT3 >10,000 nM (rodent) [29]
5-HT4L 1,000 nM (rat) [29]
5-HT5A 20,000 nM [30][29]
5-HT5B 1,000–1,585 nM (rodent) [29]
5-HT6 2,800 nM [29]
5-HT7 320–1,334 nM [30][29]
D1 190–464 nM [29]
D2 >10,000 nM [29]
D3 ?
D4 148 nM (canine) [29]
D5 2,500 nM [30][29]
α1A 6.3 nM [30]
α1B 6.3 nM [30]
α1D 16 nM [30]
α2A 372 nM (HT29) [29]
α2B 199 nM [29]
α2C 159 nM (opossum) [29]
H1 1.79 nM [29]
DAT >10,000 nM [29]
VMAT1 1,600 nM [30]
VMAT2 22–540 nM [30][6]

Pharmacodynamics

Ketanserin is a high-affinity non-selective antagonist of 5-HT2 receptors in rodents.[29][33][31][34] In addition to the 5-HT2 receptors, ketanserin is also a high affinity antagonist for the H1 receptor.[35] It has also been found to block the vesicular monoamine transporter 2 (VMAT2).[36][37]

Occupancy of the serotonin 5-HT2A receptor by ketanserin in humans has been studied.[38]

Pharmacokinetics

The bioavailability of ketanserin is 50%.[9][39][40] Its time to peak levels is 0.53 to 2.3 hours on average, with a range of 0.25 to 5.0 hours.[25][40] 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.[41] 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.[41] The plasma protein binding of ketanserin is 95.0% and it is mainly bound to albumin.[39] The elimination half-life of ketanserin is 10 to 29 hours.[42][9][40] However, a more recent study found a half-life of 3.5 hours.[25]

Chemistry

Ketanserin is a piperidinylethylquinazoline derivative.[43][44]

Synthesis

Thieme Patents:[45][46] Sino:[47] Revised:[48] Analogues[49]

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.[43][10]

History

Ketanserin was first described in the scientific literature by 1980.[43][50][51][52]

Society and culture

Names

Ketanserin is the generic name of the drug and its INN, USAN, and BAN.[10][44][43] 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.[10][44][43]

See also

References

  1. ↑ "Ketanserin: a novel cardiovascular drug". Blood Coagul Fibrinolysis 1 (2): 219–224. June 1990. PMID 2130934. 
  2. ↑ 2.0 2.1 2.2 2.3 "Ketanserin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease". Drugs 40 (6): 903–949. December 1990. doi:10.2165/00003495-199040060-00010. PMID 2079001. 
  3. ↑ 3.0 3.1 "Clinical pharmacokinetics of ketanserin". Clin Pharmacokinet 20 (4): 263–279. April 1991. doi:10.2165/00003088-199120040-00002. PMID 2036747. 
  4. ↑ Drug Injury: Liability, Analysis, and Prevention. Lawyers & Judges Publishing Company. 2005. pp. 304–. ISBN 978-0-913875-27-8. https://books.google.com/books?id=EB00rD8AqaYC&pg=PA304. 
  5. ↑ "The pharmacology of ketanserin, the first selective serotonin S2-antagonist". Drug Development Research (Wiley) 6 (4): 263–300. 1985. doi:10.1002/ddr.430060402. ISSN 0272-4391. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 ""Selective" serotonin 5-HT2A receptor antagonists". Biochem Pharmacol 200. June 2022. doi:10.1016/j.bcp.2022.115028. PMID 35381208. "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.". 
  7. ↑ The Creation of Psychopharmacology. Harvard University Press. 1 July 2009. pp. 252–253. ISBN 978-0-674-03845-5. https://books.google.com/books?id=6O2rPJnyhj0C&pg=PA252. 
  8. ↑ Breakthrough: the discovery of modern medicines at Janssen. Skyline Pub. Group. August 1989. p. 74. ISBN 978-1-56019-100-1. https://archive.org/details/breakthroughdisc0000schw. 
  9. ↑ 9.0 9.1 9.2 Cite error: Invalid <ref> tag; no text was provided for refs named Wolverton2007
  10. ↑ 10.0 10.1 10.2 10.3 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 676. ISBN 978-3-88763-101-7. https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA676. Retrieved 8 October 2024. 
  11. ↑ "Ketanserin (International database)". 6 October 2024. https://www.drugs.com/international/ketanserin.html. 
  12. ↑ ATC/DDD Index
  13. ↑ Ketanserin
  14. ↑ "Ketanserin in the treatment of protamine-induced pulmonary hypertension". Texas Heart Institute Journal 23 (4): 301–304. 1996. PMID 8969033. 
  15. ↑ "Effect of ketanserin on sodium nitroprusside requirements, arterial pressure control and heart rate following coronary artery bypass surgery". British Journal of Anaesthesia 62 (5): 527–531. May 1989. doi:10.1093/bja/62.5.527. PMID 2786422. 
  16. ↑ "Microcirculatory Imaging in Cardiac Anesthesia: Ketanserin Reduces Blood Pressure But Not Perfused Capillary Density". Journal of Cardiothoracic and Vascular Anesthesia 23 (1): 95–101. February 2009. doi:10.1053/j.jvca.2008.09.013. PMID 19058975. 
  17. ↑ "Ketanserin for Raynaud's phenomenon in progressive systemic sclerosis". The Cochrane Database of Systematic Reviews 1998 (2). 2000. doi:10.1002/14651858.CD000954. PMID 10796396. 
  18. ↑ "Analysis of neurotransmitter receptor distribution patterns in the cerebral cortex". NeuroImage 34 (4): 1317–1330. February 2007. doi:10.1016/j.neuroimage.2006.11.016. PMID 17182260. 
  19. ↑ "Serotonin receptors in the human brain--IV. Autoradiographic mapping of serotonin-2 receptors". Neuroscience 21 (1): 123–139. April 1987. doi:10.1016/0306-4522(87)90327-7. PMID 3601071. 
  20. ↑ "Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia". Synapse 42 (2): 104–114. November 2001. doi:10.1002/syn.1106. PMID 11574947. 
  21. ↑ "Imaging cortical dopamine D1 receptors using [11CNNC112 and ketanserin blockade of the 5-HT 2A receptors"]. Journal of Cerebral Blood Flow and Metabolism 30 (5): 985–993. May 2010. doi:10.1038/jcbfm.2009.269. PMID 20029452. 
  22. ↑ 22.0 22.1 "Drug-drug interactions involving classic psychedelics: A systematic review". J Psychopharmacol 38 (1): 3–18. January 2024. doi:10.1177/02698811231211219. PMID 37982394. 
  23. ↑ "Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action". NeuroReport 9 (17): 3897–3902. December 1998. doi:10.1097/00001756-199812010-00024. PMID 9875725. 
  24. ↑ "Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects". Neuropsychopharmacology 46 (3): 537–544. February 2021. doi:10.1038/s41386-020-00883-6. PMID 33059356. 
  25. ↑ 25.0 25.1 25.2 "Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants". Int J Neuropsychopharmacol 26 (2): 97–106. February 2023. doi:10.1093/ijnp/pyac075. PMID 36342343. 
  26. ↑ "Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects". Transl Psychiatry 14 (1). September 2024. doi:10.1038/s41398-024-03116-2. PMID 39349427. 
  27. ↑ "Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans". Eur Neuropsychopharmacol 26 (7): 1161–1175. July 2016. doi:10.1016/j.euroneuro.2016.03.012. PMID 27039035. 
  28. ↑ "Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile". Biol Psychiatry Cogn Neurosci Neuroimaging 9 (5): 472–489. May 2024. doi:10.1016/j.bpsc.2024.01.007. PMID 38301886. 
  29. ↑ 29.00 29.01 29.02 29.03 29.04 29.05 29.06 29.07 29.08 29.09 29.10 29.11 29.12 29.13 29.14 29.15 29.16 29.17 29.18 29.19 29.20 29.21 29.22 29.23 NIMH Psychoactive Drug Screening Program
  30. ↑ 30.00 30.01 30.02 30.03 30.04 30.05 30.06 30.07 30.08 30.09 30.10 30.11 30.12 30.13 30.14 "Ketanserin Ligand page". IUPHAR/BPS Guide to PHARMACOLOGY. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=88. 
  31. ↑ 31.0 31.1 The Role of 5-HT Systems on Memory and Dysfunctional Memory: Emergent Targets for Memory Formation and Memory Alterations. Elsevier Science. 11 March 2014. pp. 23–. ISBN 978-0-12-801083-9. https://books.google.com/books?id=x_TJAgAAQBAJ&pg=PA23. 
  32. ↑ Serotonin Receptors and their Ligands. Elsevier. 10 July 1997. pp. 118–. ISBN 978-0-08-054111-2. https://books.google.com/books?id=lfo0hGqIex0C&pg=PA118. 
  33. ↑ "Effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats". Behavioural Brain Research 219 (2): 273–279. June 2011. doi:10.1016/j.bbr.2011.01.025. PMID 21262266. 
  34. ↑ "Central serotonin receptors as targets for drug research". J Med Chem 30 (1): 1–12. January 1987. doi:10.1021/jm00384a001. PMID 3543362. "Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites". 
  35. ↑ Comparative Diagnostic Pharmacology: Clinical and Research Applications in Living-System Models. John Wiley & Sons. 9 January 2008. pp. 104–. ISBN 978-0-470-34429-3. https://books.google.com/books?id=Kar-JGFMe-AC&pg=PA104. 
  36. ↑ Handbook of the Behavioral Neurobiology of Serotonin. Academic Press. 30 December 2009. pp. 592–. ISBN 978-0-08-087817-1. https://books.google.com/books?id=aomaKqIE1jUC&pg=PA592. 
  37. ↑ Molecular Pharmacology of the Vesicular Monoamine Transporter. Advances in Pharmacology. 42. San Diego, Calif.: Academic Press. 1998. pp. 236–9 (237). doi:10.1016/s1054-3589(08)60736-x. ISBN 978-0-08-058134-7. https://books.google.com/books?id=sNQ7IA3y2kAC&pg=PA237. 
  38. ↑ "Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research". Eur Neuropsychopharmacol 88: 43–48. August 2024. doi:10.1016/j.euroneuro.2024.07.003. PMID 39121715. 
  39. ↑ 39.0 39.1 Cite error: Invalid <ref> tag; no text was provided for refs named SaitōMinami1992
  40. ↑ 40.0 40.1 40.2 Cite error: Invalid <ref> tag; no text was provided for refs named HeykantsVanPeerWoestenborghs1986
  41. ↑ 41.0 41.1 "The ABCs of psychedelics: a preclinical roadmap for drug discovery". Trends Pharmacol Sci. August 2025. doi:10.1016/j.tips.2025.07.017. PMID 40877079. "However, ketanserin’s ability to cross the blood–brain barrier varies across species: penetrance is higher in humans, monkeys, and minipigs than mice and rats, likely due to the compound being a P-glycoprotein substrate and species-related differences in P-glycoprotein-mediated removal of substances at the blood–brain barrier [111].". 
  42. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named ColdDahl2013
  43. ↑ 43.0 43.1 43.2 43.3 43.4 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&dq=ketanserin+INN&pg=PA719. Retrieved 23 April 2025. 
  44. ↑ 44.0 44.1 44.2 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&dq=ketanserin+INN&pg=PA159. Retrieved 23 April 2025. 
  45. ↑ Vandenberk J, Kennis L, Van der Aa M, Van Heertum A, US patent 4335127, issued 1982, assigned to Janssen Pharmaceutica, N.V.
  46. ↑ Signorini R, Verga A, EP patent 0098499, issued 1984, assigned to Ravizza SpA
  47. ↑ Shiwen R, et al., CN patent 106866625, issued 2017, assigned to Shanghai Ding Ya Pharmaceutical Chemistry Science And Technology Ltd)
  48. ↑ "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 of Heterocyclic Chemistry 51 (1): 151–156. January 2014. doi:10.1002/jhet.1897. .
  49. ↑ "Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding". Journal of Medicinal Chemistry 35 (26): 4903–10. December 1992. doi:10.1021/jm00104a017. PMID 1479590. 
  50. ↑ 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
  51. ↑ 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
  52. ↑ "Vascular effects of ketanserin (R 41 468), a novel antagonist of 5-HT2 serotonergic receptors". J Pharmacol Exp Ther 218 (1): 217–230. July 1981. doi:10.1016/S0022-3565(25)32655-8. PMID 6113280. 



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