Ketanserin

Ketanserin

Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	C02KD01 (WHO) QD03AX90 (WHO)
Identifiers
IUPAC name 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione
CAS Number	74050-98-9
PubChem (CID)	3822
IUPHAR/BPS	88
ChemSpider	3690
UNII	97F9DE4CT4
KEGG	D02363
ChEBI	CHEBI:6123
ChEMBL	CHEMBL51
ECHA InfoCard	100.070.598
Chemical and physical data
Formula	C22H22FN3O3
Molar mass	395.43 g/mol
3D model (Jmol)	Interactive image
SMILES c1ccc2c(c1)c(=O)n(c(=O)[nH]2)CCN3CCC(CC3)C(=O)c4ccc(cc4)F
InChI 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) Key:FPCCSQOGAWCVBH-UHFFFAOYSA-N
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Ketanserin (INN, USAN, BAN) (brand name Sufrexal; former code name R41468) is a drug used clinically as an antihypertensive agent and in scientific research to study the serotonin system; specifically, the 5-HT₂ receptor family.^[1] It was discovered at Janssen Pharmaceutica in 1980.

Medical use

It is classified as an antihypertensive by the World Health Organization^[2] and the National Institute of Health.^[3]

It has been used to reverse pulmonary hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose).^[4]

The reduction in hypertension is not associated with reflex tachycardia.^[5]

It has been used in cardiac surgery.^[6]

Research use

With tritium (³H) radioactively labeled ketanserin is used as a radioligand for serotonin 5-HT₂ receptors, e.g. in receptor binding assays and autoradiography.^[7] This radio labeling has enabled the study of serotonin-2A receptor distribution in the human brain.^[8]

An autoradiography study of the human cerebellum has found an increasing binding of H-3-ketanserin with age (from below 50 femtomol per milligram tissue at around 30 years og age to over 100 above 75 years).^[9] 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.^[10]

Pharmacology

Ketanserin is a high-affinity non-selective antagonist of 5-HT₂ receptors in rodents.^{[11] [12]} (K_i 5-HT_2A= 2-3 nM; K_i 5-HT_2C= 28 nM).^[11][13] In non-human primates and humans, however, ketanserin is considered a selective antagonist for the 5-HT_2A over the 5-HT_2C receptor^[11] (K_i 5-HT_2A= 2-3 nM; K_i 5-HT_2C= 130 nM)

In addition, ketanserin is also a high affinity antagonist for the H₁ receptor (K_i = 2 nM),^[11][14] and has measurable affinity for several other receptors:

• α₁-adrenergic receptors (K_i = ~40 nM)^[14]
• α₂-adrenergic receptors = ~200 nM)
• 5-HT_1D receptors (K_i = ? nM) ^[13][15]
• 5-HT_2B receptors (K_i = ? nM)^[16]
• 5-HT₆ receptors (K_i = ~300 nM)^[17]
• 5-HT₇ receptors (K_i = ? nM)^[13]
• D₁ receptors (~300 nM)^[14]
• D₂ receptors (K_i = ~500 nM) receptors.^[11][14]

It also blocks the vesicular monoamine transporter (VMAT2).^[18][19]

References

1. Gopi Doctor Ahuja (2005). Drug Injury: Liability, Analysis, and Prevention. Lawyers & Judges Publishing Company. pp. 304–. ISBN 978-0-913875-27-8.
2. ATC/DDD Index
3. Ketanserin
4. van der Starre PJ, Solinas C (1996). "Ketanserin in the treatment of protamine-induced pulmonary hypertension". Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 23 (4): 301–4. PMC 325377. PMID 8969033.
5. 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): 527–31. doi:10.1093/bja/62.5.527. PMID 2786422.
6. Elbers PW, Ozdemir A, van Iterson M, van Dongen EP, Ince C (December 2008). "Microcirculatory Imaging in Cardiac Anesthesia: Ketanserin Reduces Blood Pressure But Not Perfused Capillary Density". J. Cardiothorac. Vasc. Anesth. 23 (1): 95–101. doi:10.1053/j.jvca.2008.09.013. PMID 19058975.
7. Simon B. Eickhoff, Axel Schleicher, Filip Scheperjans, Nicola Palomero-Gallagher & Karl Zilles (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.
8. A. Pazos; A. Probst; J. M. Palacios (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.
9. Sharon L. Eastwood; Philip W. J. Burnet; Rebecca Gittins; Kate Baker; Paul J. Harrison (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.
10. Catafau AM, Searle GE, Bullich S, Gunn RN, Rabiner EA, Herance R, Radua J, Farre M, Laruelle M (2010). "Imaging cortical dopamine D1 receptors using 11C NNC112 and ketanserin blockade of the 5-HT 2A receptors". J Cereb Blood Flow Metab. 30 (5): 985–93. doi:10.1038/jcbfm.2009.269. PMID 20029452.
11. NIMH Psychoactive Drug Screening Program
12. Creed-Carson M; Oraha A. Norbrega JN. (2011). "Effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats". Behav Brain Res. 219: 273–279. doi:10.1016/j.bbr.2011.01.025. PMID 21262266.
13. Alfredo Meneses (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.
14. C.P. Coyne (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.
15. B. Olivier; I. van Wijngaarden; W. Soudijn (10 July 1997). Serotonin Receptors and their Ligands. Elsevier. pp. 118–. ISBN 978-0-08-054111-2.
16. Mark Chapman (2007). Evaluation of the Role of Serotonin in Pulmonary Arterial Hypertension in Broilers Induced by Bacterial Lipopolysaccharide and Cellulose Microparticles. ProQuest. pp. 31–. ISBN 978-0-549-36052-0.
17. Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 388–. ISBN 978-1-60913-345-0.
18. Christian P. Muller; Barry Jacobs (30 December 2009). Handbook of the Behavioral Neurobiology of Serotonin. Academic Press. pp. 592–. ISBN 978-0-08-087817-1.
19. Catecholamines: Bridging Basic Science with Clinical Medicine: Bridging Basic Science with Clinical Medicine. Academic Press. 20 October 1997. pp. 237–. ISBN 978-0-08-058134-7.