Ketanserin

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Ketanserin
Ketanserin.png
Ketanserin 3D.png
Clinical data
Trade names Sufrexal, Serefrex
Other namesR-41468; R41468; R-41,468; KJK-945; R-49945; R49945
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 50% [1] [2]
Protein binding 95% (mainly albumin [2] [3]
Metabolism Extensive [3]
Metabolites • Ketanserin-ol [3]
Elimination half-life 10–29 hours [4] [1] [2]
Excretion Urine; 2% unchanged [3]
Identifiers
  • 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.070.598 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H22FN3O3
Molar mass 395.434 g·mol−1
3D model (JSmol)
  • c1ccc2c(c1)c(=O)n(c(=O)[nH]2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F
  • InChI=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) Yes check.svgY
  • Key:FPCCSQOGAWCVBH-UHFFFAOYSA-N Yes check.svgY
   (verify)

Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospastic disorders. [5] [6] [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. [7] The drug is taken by mouth. [6] [3]

Contents

Side effects of ketanserin include dizziness, tiredness, edema, dry mouth, weight gain, and QT interval prolongation. [6] Ketanserin acts as a selective antagonist of the serotonin 5-HT2A, α1-adrenergic, and histamine H1 receptors. [6] [8] [9] It also shows lower affinity for various other targets. [9]

Ketanserin was discovered at Janssen Pharmaceutica in 1980. [10] [11] It was the first serotonin 5-HT2A receptor antagonist to be discovered that showed selectivity over other serotonin receptors. [9] The drug is not available in the United States [1] and is mostly no longer marketed throughout the rest of the world. [12] [13]

Uses

Medical uses

Ketanserin is classified as an antihypertensive by the World Health Organization [14] and the National Institute of Health. [15]

It has been used to reverse pulmonary hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose). [16]

The reduction in hypertension is not associated with reflex tachycardia. [17]

It has been used in cardiac surgery. [18]

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. [19]

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. [20] This radio-labeling has enabled the study of serotonin 5-HT2A receptor distribution in the human brain. [21]

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). [22] 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. [23]

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. [24] Ketanserin has been found to block the psychedelic effects of psilocybin, [25] lysergic acid diethylamide (LSD), [26] [27] mescaline, [28] and ayahuasca (dimethyltryptamine) [29] in clinical studies. [24] [30]

Pharmacology

Human molecular targets of ketanserin [31] [32] [9]
TargetAffinity (Ki)Ref(s)
5-HT1A 1,044–>10,000 nM [32] [31]
5-HT1B 2,515–6,300 nM [32] [31]
5-HT1D 32–>10,000 nM [32] [33] [34]
5-HT1E >10,000 nM [31]
5-HT1F 1.25–>10,000 nM [31]
5-HT2A 0.20–9.8 nM [32] [31]
5-HT2B 200–3,236 nM [32] [31]
5-HT2C 17–186 nM [32] [31]
5-HT3 >10,000 nM (rodent) [31]
5-HT4L 1,000 nM (rat) [31]
5-HT5A 20,000 nM [32] [31]
5-HT5B 1,000–1,585 nM (rodent) [31]
5-HT6 2,800 nM [31]
5-HT7 320–1,334 nM [32] [31]
D1 190–464 nM [31]
D2 >10,000 nM [31]
D3 ?
D4 148 nM (canine) [31]
D5 2,500 nM [32] [31]
α1A 6.3 nM [32]
α1B 6.3 nM [32]
α1D 16 nM [32]
α2A 372 nM (HT29) [31]
α2B 199 nM [31]
α2C 159 nM (opossum) [31]
H1 1.79 nM [31]
DAT >10,000 nM [31]
VMAT1 1,600 nM [32]
VMAT2 22–540 nM [32] [9]

Pharmacodynamics

Ketanserin is a high-affinity non-selective antagonist of 5-HT2 receptors in rodents. [31] [35] [33] [36] In addition to the 5-HT2 receptors, ketanserin is also a high affinity antagonist for the H1 receptor. [37] It has also been found to block the vesicular monoamine transporter 2 (VMAT2). [38] [39]

Occupancy of the serotonin 5-HT2A receptor by ketanserin in humans has been studied. [40]

Pharmacokinetics

The bioavailability of ketanserin is 50%. [1] [2] The plasma protein binding of ketanserin is 95.0% and it is mainly bound to albumin. [2] The elimination half-life of ketanserin is 10 to 29 hours. [4] [1]

Chemistry

Ketanserin is a piperidinylethylquinazoline derivative. [41] [42]

Synthesis

Thieme Patents: Sino: Revised: Analogues Ketanserin synthesis.svg
Thieme Patents: Sino: Revised: Analogues

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. [41] [12]

History

Ketanserin was first described in the scientific literature by 1980. [41] [48] [49] [50]

Society and culture

Names

Ketanserin is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name. [12] [42] [41] 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. [12] [42] [41]

References

  1. 1 2 3 4 5 Wolverton SE (8 March 2007). Comprehensive Dermatologic Drug Therapy (2 ed.). Elsevier Health Sciences. ISBN   978-1-4377-2070-9.
  2. 1 2 3 4 5 Hideya Saitō, Masaru Minami, eds. (1992). Antihypertensive Drugs Today. VSP. pp. 191–. ISBN   978-90-6764-140-1. OCLC   231351327.
  3. 1 2 3 4 5 6 Persson B, Heykants J, Hedner T (April 1991). "Clinical pharmacokinetics of ketanserin". Clin Pharmacokinet. 20 (4): 263–279. doi:10.2165/00003088-199120040-00002. PMID   2036747.
  4. 1 2 Cold GE, Dahl BL (11 November 2013). Topics in Neuroanaesthesia and Neurointensive Care: Experimental and Clinical Studies upon Cerebral Circulation, Metabolism and Intracranial Pressure. Springer Science & Business Media. pp. 193–. ISBN   978-3-662-04845-0. OCLC   1076237896.
  5. ↑ Symoens J (June 1990). "Ketanserin: a novel cardiovascular drug". Blood Coagul Fibrinolysis. 1 (2): 219–224. PMID   2130934.
  6. 1 2 3 4 Brogden RN, Sorkin EM (December 1990). "Ketanserin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease". Drugs. 40 (6): 903–949. doi:10.2165/00003495-199040060-00010. PMID   2079001.
  7. ↑ O'Donnell J, Ahuja GD (2005). Drug Injury: Liability, Analysis, and Prevention. Lawyers & Judges Publishing Company. pp. 304–. ISBN   978-0-913875-27-8.
  8. ↑ Awouters F (1985). "The pharmacology of ketanserin, the first selective serotonin S2-antagonist". Drug Development Research. 6 (4). Wiley: 263–300. doi:10.1002/ddr.430060402. ISSN   0272-4391.
  9. 1 2 3 4 5 Casey AB, Cui M, Booth RG, Canal CE (June 2022). ""Selective" serotonin 5-HT2A receptor antagonists". Biochem Pharmacol. 200 115028. doi:10.1016/j.bcp.2022.115028. PMC   9252399 . 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.
  10. ↑ Healy D (1 July 2009). The Creation of Psychopharmacology. Harvard University Press. pp. 252–253. ISBN   978-0-674-03845-5.
  11. ↑ Schwartz H (August 1989). Breakthrough: the discovery of modern medicines at Janssen . Skyline Pub. Group. p.  74. ISBN   978-1-56019-100-1.
  12. 1 2 3 4 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 676. ISBN   978-3-88763-101-7 . Retrieved 8 October 2024.
  13. ↑ "Ketanserin (International database)". Drugs.com. 6 October 2024. Retrieved 8 October 2024.
  14. ↑ ATC/DDD Index
  15. ↑ Ketanserin
  16. ↑ van der Starre PJ, Solinas C (1996). "Ketanserin in the treatment of protamine-induced pulmonary hypertension". Texas Heart Institute Journal. 23 (4): 301–304. PMC   325377 . PMID   8969033.
  17. ↑ Hodsman NB, Colvin JR, Kenny GN (May 1989). "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. doi: 10.1093/bja/62.5.527 . PMID   2786422.
  18. ↑ Elbers PW, Ozdemir A, van Iterson M, van Dongen EP, Ince C (February 2009). "Microcirculatory Imaging in Cardiac Anesthesia: Ketanserin Reduces Blood Pressure But Not Perfused Capillary Density". Journal of Cardiothoracic and Vascular Anesthesia. 23 (1): 95–101. doi:10.1053/j.jvca.2008.09.013. PMID   19058975.
  19. ↑ Pope J, Fenlon D, Thompson A, Shea B, Furst D, Wells G, et al. (2000). "Ketanserin for Raynaud's phenomenon in progressive systemic sclerosis". The Cochrane Database of Systematic Reviews. 1998 (2): CD000954. doi:10.1002/14651858.CD000954. PMC   7032891 . PMID   10796396.{{cite journal}}: CS1 maint: article number as page number (link)
  20. ↑ Eickhoff SB, Schleicher A, Scheperjans F, Palomero-Gallagher N, Zilles K (February 2007). "Analysis of neurotransmitter receptor distribution patterns in the cerebral cortex". NeuroImage. 34 (4): 1317–1330. doi:10.1016/j.neuroimage.2006.11.016. PMID   17182260. S2CID   23363050.
  21. ↑ Pazos A, Probst A, Palacios JM (April 1987). "Serotonin receptors in the human brain--IV. Autoradiographic mapping of serotonin-2 receptors". Neuroscience. 21 (1): 123–139. doi:10.1016/0306-4522(87)90327-7. PMID   3601071. S2CID   23711420.
  22. ↑ Eastwood SL, Burnet PW, Gittins R, Baker K, Harrison PJ (November 2001). "Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia". Synapse. 42 (2): 104–114. doi:10.1002/syn.1106. PMID   11574947. S2CID   40304220.
  23. ↑ Catafau AM, Searle GE, Bullich S, Gunn RN, Rabiner EA, Herance R, et al. (May 2010). "Imaging cortical dopamine D1 receptors using [11C]NNC112 and ketanserin blockade of the 5-HT 2A receptors". Journal of Cerebral Blood Flow and Metabolism. 30 (5): 985–993. doi:10.1038/jcbfm.2009.269. PMC   2949183 . PMID   20029452.
  24. 1 2 Halman A, Kong G, Sarris J, Perkins D (January 2024). "Drug-drug interactions involving classic psychedelics: A systematic review". J Psychopharmacol. 38 (1): 3–18. doi:10.1177/02698811231211219. PMC   10851641 . PMID   37982394.
  25. ↑ Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D (December 1998). "Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action". NeuroReport. 9 (17): 3897–3902. doi:10.1097/00001756-199812010-00024. PMID   9875725.
  26. ↑ Holze F, Vizeli P, Ley L, Müller F, Dolder P, Stocker M, et al. (February 2021). "Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects". Neuropsychopharmacology. 46 (3): 537–544. doi:10.1038/s41386-020-00883-6. PMC   8027607 . PMID   33059356.
  27. ↑ Becker AM, Klaiber A, Holze F, Istampoulouoglou I, Duthaler U, Varghese N, et al. (February 2023). "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. doi:10.1093/ijnp/pyac075. PMC   9926053 . PMID   36342343.
  28. ↑ Klaiber A, Schmid Y, Becker AM, Straumann I, Erne L, Jelusic A, et al. (September 2024). "Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects". Transl Psychiatry. 14 (1) 395. doi:10.1038/s41398-024-03116-2. PMC   11442856 . PMID   39349427.
  29. ↑ Valle M, Maqueda AE, Rabella M, Rodríguez-Pujadas A, Antonijoan RM, Romero S, et al. (July 2016). "Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans". Eur Neuropsychopharmacol. 26 (7): 1161–1175. doi:10.1016/j.euroneuro.2016.03.012. hdl: 2117/101863 . PMID   27039035.
  30. ↑ Holze F, Singh N, Liechti ME, D'Souza DC (May 2024). "Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile". Biol Psychiatry Cogn Neurosci Neuroimaging. 9 (5): 472–489. doi: 10.1016/j.bpsc.2024.01.007 . PMID   38301886.
  31. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 NIMH Psychoactive Drug Screening Program
  32. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Ketanserin Ligand page". IUPHAR/BPS Guide to PHARMACOLOGY.
  33. 1 2 Meneses A (11 March 2014). The Role of 5-HT Systems on Memory and Dysfunctional Memory: Emergent Targets for Memory Formation and Memory Alterations. Elsevier Science. pp. 23–. ISBN   978-0-12-801083-9.
  34. ↑ Olivier B, van Wijngaarden I, Soudijn W (10 July 1997). Serotonin Receptors and their Ligands. Elsevier. pp. 118–. ISBN   978-0-08-054111-2.
  35. ↑ Creed-Carson M, Oraha A, Nobrega JN (June 2011). "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. doi:10.1016/j.bbr.2011.01.025. PMID   21262266. S2CID   205882443.
  36. ↑ Glennon RA (January 1987). "Central serotonin receptors as targets for drug research". J Med Chem. 30 (1): 1–12. doi:10.1021/jm00384a001. PMID   3543362. Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
  37. ↑ Coyne CP (9 January 2008). Comparative Diagnostic Pharmacology: Clinical and Research Applications in Living-System Models. John Wiley & Sons. pp. 104–. ISBN   978-0-470-34429-3.
  38. ↑ Muller CP, Jacobs B (30 December 2009). Handbook of the Behavioral Neurobiology of Serotonin. Academic Press. pp. 592–. ISBN   978-0-08-087817-1.
  39. ↑ Henry JP, Sagné C, Botton D, Isambert MF, Gasnier B (1998). Molecular Pharmacology of the Vesicular Monoamine Transporter. Advances in Pharmacology. Vol. 42. San Diego, Calif.: Academic Press. pp. 236–9 (237). doi:10.1016/s1054-3589(08)60736-x. ISBN   978-0-08-058134-7. PMID   9327887.
  40. ↑ Holze F, Madsen MK, Svarer C, Gillings N, Stenbaek DS, Rudin D, et al. (August 2024). "Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research". Eur Neuropsychopharmacol. 88: 43–48. doi:10.1016/j.euroneuro.2024.07.003. PMID   39121715.
  41. 1 2 3 4 5 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. ISBN   978-1-4757-2085-3 . Retrieved 23 April 2025.
  42. 1 2 3 Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. ISBN   978-94-011-4439-1 . Retrieved 23 April 2025.
  43. ↑ US 4335127,Vandenberk J, Kennis L, Van der Aa M, Van Heertum A,issued 1982, assigned to Janssen Pharmaceutica, N.V.
  44. ↑ EP 0098499,Signorini R, Verga A,issued 1984, assigned to Ravizza SpA
  45. ↑ CN 106866625,Shiwen R, et al.,issued 2017, assigned to Shanghai Ding Ya Pharmaceutical Chemistry Science And Technology Ltd)
  46. ↑ Fakhraian H, Heydary M (January 2014). "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. doi:10.1002/jhet.1897..
  47. ↑ Herndon JL, Ismaiel A, Ingher SP, Teitler M, Glennon RA (December 1992). "Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding". Journal of Medicinal Chemistry. 35 (26): 4903–10. doi:10.1021/jm00104a017. PMID   1479590.
  48. ↑ 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
  49. ↑ 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
  50. ↑ Van Nueten JM, Janssen PA, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM (July 1981). "Vascular effects of ketanserin (R 41 468), a novel antagonist of 5-HT2 serotonergic receptors". J Pharmacol Exp Ther. 218 (1): 217–230. doi:10.1016/S0022-3565(25)32655-8. PMID   6113280.
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