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Ketanserin

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Ketanserin
Clinical data
Trade namesSufrexal
Other namesR-41468; R41468; R-41,468; KJK-945; R-49945; R49945
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50%[1][2]
Protein binding95% (mainly albumin[2][3]
MetabolismExtensive[3]
Metabolites• Ketanserin-ol[3]
Elimination half-life10–29 hours[4][1][2]
ExcretionUrine; 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 InfoCard100.070.598 Edit this at Wikidata
Chemical and physical data
FormulaC22H22FN3O3
Molar mass395.434 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) checkY
  • Key:FPCCSQOGAWCVBH-UHFFFAOYSA-N checkY
  (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]

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

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Medical uses

[edit]

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

[edit]

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 ayahausca (dimethyltryptamine)[29] in clinical studies.[24][30]

Pharmacology

[edit]
Human molecular targets of ketanserin[31][32][9]
Target Affinity (Ki) Ref(s)
α1A-adrenergic 6.3 nM [32]
α1B-adrenergic 6.3 nM [32]
α1D-adrenergic 16 nM [32]
α2A-adrenergic 372 nM (HT29) [31]
α2B-adrenergic 199 nM [31]
α2C-adrenergic 159 nM (opossum) [31]
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]
H1 1.79 nM [31]
DAT >10,000 nM [31]
VMAT1 1,600 nM [32]
VMAT2 22–540 nM [32][9]

Pharmacodynamics

[edit]

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

Occupancy of the serotonin 5-HT2A receptor by ketanserin in humans has been studied.[39]

Pharmacokinetics

[edit]

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

[edit]

Synthesis

[edit]
Thieme Patents:[40][41] Sino:[42] Revised:[43] Analogues[44]

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).

Society and culture

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Names

[edit]

Ketanserin is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name.[12] It is also known by its major brand name Sufrexal and by its former developmental code names R-41468, KJK-945, and R-49945.[12]

See also

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References

[edit]
  1. ^ a b c d e Wolverton SE (8 March 2007). Comprehensive Dermatologic Drug Therapy (2 ed.). Elsevier Health Sciences. ISBN 978-1-4377-2070-9.
  2. ^ a b c d e Hideya Saitō, Masaru Minami, eds. (1992). Antihypertensive Drugs Today. VSP. pp. 191–. ISBN 978-90-6764-140-1. OCLC 231351327.
  3. ^ a b c d e f 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. ^ a b 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. ^ a b c d 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. ^ a b c d e 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.
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  13. ^ "Ketanserin (International database)". Drugs.com. 6 October 2024. Retrieved 8 October 2024.
  14. ^ ATC/DDD Index
  15. ^ Ketanserin
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  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, Silman A (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.
  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.
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  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.
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  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, Duthaler U, Varghese N, Eckert A, Borgwardt S, Liechti ME (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, Eckert A, Liechti ME (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.
  28. ^ Klaiber A, Schmid Y, Becker AM, Straumann I, Erne L, Jelusic A, Thomann J, Luethi D, Liechti ME (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, Alonso JF, Mañanas MÀ, Barker S, Friedlander P, Feilding A, Riba J (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. 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.
  31. ^ a b c d e f g h i j k l m n o p q r s t u v w x NIMH Psychoactive Drug Screening Program
  32. ^ a b c d e f g h i j k l m n o "Ketanserin Ligand page". IUPHAR/BPS Guide to PHARMACOLOGY.
  33. ^ a b 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. ^ 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.
  37. ^ Muller CP, Jacobs B (30 December 2009). Handbook of the Behavioral Neurobiology of Serotonin. Academic Press. pp. 592–. ISBN 978-0-08-087817-1.
  38. ^ 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.
  39. ^ Holze F, Madsen MK, Svarer C, Gillings N, Stenbaek DS, Rudin D, Duthaler U, Liechti ME, Fisher PM, Knudsen GM (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.
  40. ^ US 4335127, Vandenberk J, Kennis L, Van der Aa M, Van Heertum A, issued 1982, assigned to Janssen Pharmaceutica, N.V. 
  41. ^ EP 0098499, Signorini R, Verga A, issued 1984, assigned to Ravizza SpA 
  42. ^ CN 106866625, Shiwen R, et al., issued 2017, assigned to Shanghai Ding Ya Pharmaceutical Chemistry Science And Technology Ltd) 
  43. ^ 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..
  44. ^ 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.
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