Ketanserin Explained

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 by mouth.

Side effects of ketanserin include dizziness, tiredness, edema, dry mouth, weight gain, and QT interval prolongation. Ketanserin acts as a selective antagonist of the serotonin 5-HT_2A, α₁-adrenergic, and histamine H₁ receptors.^{[5] [6]} It also shows lower affinity for various other targets.

Ketanserin was discovered at Janssen Pharmaceutica in 1980.^{[7] [8]} It was the first serotonin 5-HT_2A receptor antagonist to be discovered that showed selectivity over other serotonin receptors. The drug is not available in the United States and is mostly no longer marketed throughout the rest of the world.^[9]

Uses

Medical uses

Ketanserin is classified as an antihypertensive by the World Health Organization^[10] and the National Institute of Health.^[11]

It has been used to reverse pulmonary hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose).^[12]

The reduction in hypertension is not associated with reflex tachycardia.^[13]

It has been used in cardiac surgery.^[14]

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.^[15]

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.^[16] This radio-labeling has enabled the study of serotonin 5-HT_2A receptor distribution in the human brain.^[17]

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).^[18] 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.^[19]

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.^[20] Ketanserin has been found to block the psychedelic effects of psilocybin,^[21] lysergic acid diethylamide (LSD),^{[22] [23]} mescaline,^[24] and ayahausca (dimethyltryptamine)^[25] in clinical studies.^[26]

Pharmacology

Human molecular targets of ketanserin^{[27] [28]} ! Target! Affinity (K_i)! Ref(s)

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

Pharmacodynamics

Ketanserin is a high-affinity non-selective antagonist of 5-HT₂ receptors in rodents,^{[30] [31]} In addition to the 5-HT₂ receptors, ketanserin is also a high affinity antagonist for the H₁ receptor.^[32] It has also been found to block the vesicular monoamine transporter 2 (VMAT2).^{[33] [34]}

Occupancy of the serotonin 5-HT_2A receptor by ketanserin in humans has been studied.^[35]

Pharmacokinetics

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

Chemistry

Synthesis

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

Names

Ketanserin is the generic name of the drug and its,, .^[36] It is also known by its major brand name Sufrexal and by its former developmental code names R-41468, KJK-945, and R-49945.

See also

• Altanserin
• Pirenperone
• Setoperone
• Pelanserin

Notes and References

1. Symoens J . Ketanserin: a novel cardiovascular drug . Blood Coagul Fibrinolysis . 1 . 2 . 219–224 . June 1990 . 2130934 .
2. Brogden RN, Sorkin EM . 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 . 2079001 . 10.2165/00003495-199040060-00010 .
3. Persson B, Heykants J, Hedner T . Clinical pharmacokinetics of ketanserin . Clin Pharmacokinet . 20 . 4 . 263–279 . April 1991 . 2036747 . 10.2165/00003088-199120040-00002 .
4. Book: O'Donnell J, Ahuja GD . Drug Injury: Liability, Analysis, and Prevention. 2005. Lawyers & Judges Publishing Company. 978-0-913875-27-8. 304–.
5. Awouters . Frans . The pharmacology of ketanserin, the first selective serotonin S₂‐antagonist . Drug Development Research . Wiley . 6 . 4 . 1985 . 0272-4391 . 10.1002/ddr.430060402 . 263–300.
6. Casey AB, Cui M, Booth RG, Canal CE . "Selective" serotonin 5-HT2A receptor antagonists . Biochem Pharmacol . 200 . 115028 . June 2022 . 35381208 . 9252399 . 10.1016/j.bcp.2022.115028 . 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. Book: Healy D . The Creation of Psychopharmacology. 1 July 2009. Harvard University Press. 978-0-674-03845-5. 252–253.
8. Book: Schwartz H . Breakthrough: the discovery of modern medicines at Janssen . registration. August 1989. Skyline Pub. Group. 978-1-56019-100-1. 74.
9. Web site: Ketanserin (International database) . Drugs.com . 6 October 2024 . 8 October 2024.
10. http://www.whocc.no/atc_ddd_index/?code=C02KD01 ATC/DDD Index
11. https://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?mode=&term=Ketanserin Ketanserin
12. van der Starre PJ, Solinas C . Ketanserin in the treatment of protamine-induced pulmonary hypertension . Texas Heart Institute Journal . 23 . 4 . 301–304 . 1996 . 8969033 . 325377 .
13. Hodsman NB, Colvin JR, Kenny GN . 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 . 2786422 . 10.1093/bja/62.5.527 . free .
14. Elbers PW, Ozdemir A, van Iterson M, van Dongen EP, Ince C . 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 . 19058975 . 10.1053/j.jvca.2008.09.013 .
15. Pope J, Fenlon D, Thompson A, Shea B, Furst D, Wells G, Silman A . Ketanserin for Raynaud's phenomenon in progressive systemic sclerosis . The Cochrane Database of Systematic Reviews . 2 . CD000954 . 2000 . 1998 . 10796396 . 7032891 . 10.1002/14651858.CD000954 .
16. Eickhoff SB, Schleicher A, Scheperjans F, Palomero-Gallagher N, Zilles K . Analysis of neurotransmitter receptor distribution patterns in the cerebral cortex . NeuroImage . 34 . 4 . 1317–1330 . February 2007 . 17182260 . 10.1016/j.neuroimage.2006.11.016 . 23363050 .
17. Pazos A, Probst A, Palacios JM . Serotonin receptors in the human brain--IV. Autoradiographic mapping of serotonin-2 receptors . Neuroscience . 21 . 1 . 123–139 . April 1987 . 3601071 . 10.1016/0306-4522(87)90327-7 . 23711420 .
18. Eastwood SL, Burnet PW, Gittins R, Baker K, Harrison PJ . Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia . Synapse . 42 . 2 . 104–114 . November 2001 . 11574947 . 10.1002/syn.1106 . 40304220 .
19. Catafau AM, Searle GE, Bullich S, Gunn RN, Rabiner EA, Herance R, Radua J, Farre M, Laruelle M . 6 . 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 . May 2010 . 20029452 . 2949183 . 10.1038/jcbfm.2009.269 .
20. Halman A, Kong G, Sarris J, Perkins D . Drug-drug interactions involving classic psychedelics: A systematic review . J Psychopharmacol . 38 . 1 . 3–18 . January 2024 . 37982394 . 10851641 . 10.1177/02698811231211219 .
21. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D . Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action . NeuroReport . 9 . 17 . 3897–3902 . December 1998 . 9875725 . 10.1097/00001756-199812010-00024 .
22. Holze F, Vizeli P, Ley L, Müller F, Dolder P, Stocker M, Duthaler U, Varghese N, Eckert A, Borgwardt S, Liechti ME . 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 . 33059356 . 8027607 . 10.1038/s41386-020-00883-6 .
23. Becker AM, Klaiber A, Holze F, Istampoulouoglou I, Duthaler U, Varghese N, Eckert A, Liechti ME . 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 . 9926053 . 10.1093/ijnp/pyac075 .
24. Klaiber A, Schmid Y, Becker AM, Straumann I, Erne L, Jelusic A, Thomann J, Luethi D, Liechti ME . Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects . Transl Psychiatry . 14 . 1 . 395 . September 2024 . 39349427 . 11442856 . 10.1038/s41398-024-03116-2 .
25. 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 . 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 . 27039035 . 10.1016/j.euroneuro.2016.03.012 . 2117/101863 . free .
26. Holze F, Singh N, Liechti ME, D'Souza DC . Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile . Biol Psychiatry Cogn Neurosci Neuroimaging . 9 . 5 . 472–489 . May 2024 . 10.1016/j.bpsc.2024.01.007 . free .
27. https://pdsp.unc.edu/databases/pdsp.php NIMH Psychoactive Drug Screening Program
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31. Book: Meneses A . The Role of 5-HT Systems on Memory and Dysfunctional Memory: Emergent Targets for Memory Formation and Memory Alterations. 11 March 2014. Elsevier Science. 978-0-12-801083-9. 23–.
32. Book: Coyne CP . Comparative Diagnostic Pharmacology: Clinical and Research Applications in Living-System Models. 9 January 2008. John Wiley & Sons. 978-0-470-34429-3. 104–.
33. Book: Muller CP, Jacobs B . Handbook of the Behavioral Neurobiology of Serotonin. 30 December 2009. Academic Press. 978-0-08-087817-1. 592–.
34. Book: Henry JP, Sagné C, Botton D, Isambert MF, Gasnier B . Molecular Pharmacology of the Vesicular Monoamine Transporter . Advances in Pharmacology . San Diego, Calif. . 42 . 236–9 (237) . 1998 . 9327887 . 10.1016/s1054-3589(08)60736-x . Academic Press. 978-0-08-058134-7 .
35. Holze F, Madsen MK, Svarer C, Gillings N, Stenbaek DS, Rudin D, Duthaler U, Liechti ME, Fisher PM, Knudsen GM . Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research . Eur Neuropsychopharmacol . 88 . 43–48 . August 2024 . 10.1016/j.euroneuro.2024.07.003 .
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