Ketanserin

Last updated

Ketanserin
Ketanserin.png
Ketanserin 3D.png
Clinical data
Trade names Sufrexal
Other namesR41468; R-41468; R-41,468
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 95.0% (mainly albumin [2]
Elimination half-life 10–29 hours [3] [1] [2]
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 (INN, USAN, BAN) (brand name Sufrexal; former developmental code name R41468) is a drug used clinically as an antihypertensive agent and in scientific research to study the serotonergic system; specifically, the 5-HT2 receptor family. [4] It was discovered at Janssen Pharmaceutica in 1980. [5] [6] It is not available in the United States. [1]

Contents

Uses

Medical uses

Ketanserin is classified as an antihypertensive by the World Health Organization [7] and the National Institute of Health. [8]

It has been used to reverse pulmonary hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose). [9]

The reduction in hypertension is not associated with reflex tachycardia. [10]

It has been used in cardiac surgery. [11]

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. [12]

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. [13] This radio-labeling has enabled the study of serotonin 5-HT2A receptor distribution in the human brain. [14]

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). [15] 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. [16]

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. [17]

Pharmacology

Human molecular targets of ketanserin [18] [19]
TargetAffinity (Ki)Ref(s)
α1A-adrenergic 6.3 nM [19]
α1B-adrenergic 6.3 nM [19]
α1D-adrenergic 16 nM [19]
α2A-adrenergic 372 nM (HT29) [18]
α2B-adrenergic 199 nM [18]
α2C-adrenergic 159 nM (opossum) [18]
5-HT1A 1,044–>10,000 nM [19] [18]
5-HT1B 2,515–6,300 nM [19] [18]
5-HT1D 32–>10,000 nM [19] [20] [21]
5-HT1E >10,000 nM [18]
5-HT1F 1.25–>10,000 nM [18]
5-HT2A 0.20–9.8 nM [19] [18]
5-HT2B 200–3,236 nM [19] [18]
5-HT2C 17–186 nM [19] [18]
5-HT3 >10,000 nM (rodent) [18]
5-HT4L 1,000 nM (rat) [18]
5-HT5A 20,000 nM [19] [18]
5-HT5B 1,000–1,585 nM (rodent) [18]
5-HT6 2,800 nM [18]
5-HT7 320–1,334 nM [19] [18]
D1 190–464 nM [18]
D2 >10,000 nM [18]
D3  ?
D4 148 nM (canine) [18]
D5 2,500 nM [19] [18]
H1 1.79 nM [18]
DAT >10,000 nM [18]
VMAT1 1,600 nM [19]
VMAT2 500 nM [19]

Pharmacodynamics

Ketanserin is a high-affinity non-selective antagonist of 5-HT2 receptors in rodents, [18] [22] [20] In addition to the 5-HT2 receptors, ketanserin is also a high affinity antagonist for the H1 receptor. [23] It has also been found to block the vesicular monoamine transporter 2 (VMAT2). [24] [25]

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. [3] [1]

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).

See also

Related Research Articles

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

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Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and in the treatment of migraine. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.

<span class="mw-page-title-main">Ritanserin</span> Chemical compound

Ritanserin, also known by its developmental code name R-55667, is a serotonin antagonist medication described as an anxiolytic, antidepressant, antiparkinsonian agent, and antihypertensive agent. It was chiefly investigated as a drug to treat insomnia, especially to enhance sleep quality by significantly increasing slow wave sleep by virtue of potent and concomitant 5HT2a and 5HT2c antagonism

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.

<span class="mw-page-title-main">Mianserin</span> Antidepressant

Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closely related to mirtazapine, both chemically and in terms of its actions and effects, although there are significant differences between the two drugs.

The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT2 subfamily consists of three G protein-coupled receptors (GPCRs) which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C. For more information, please see the respective main articles of the individual subtypes:

<span class="mw-page-title-main">Pipamperone</span> Antipsychotic drug

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A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action of serotonin and serotonergic drugs at serotonin (5-HT) receptors.

5-HT<sub>2B</sub> receptor Mammalian protein found in Homo sapiens

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

<span class="mw-page-title-main">Altanserin</span> Chemical compound

Altanserin is a compound that binds to the 5-HT2A receptor. Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography (PET) studies of the brain, i.e., studies of the 5-HT2A neuroreceptors. Besides human neuroimaging studies altanserin has also been used in the study of rats.

<span class="mw-page-title-main">WAY-100635</span> Chemical compound

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<span class="mw-page-title-main">Sarpogrelate</span> Chemical compound

Sarpogrelate is a drug which acts as an antagonist at the 5HT2A and 5-HT2B receptors. It blocks serotonin-induced platelet aggregation, and has applications in the treatment of many diseases including diabetes mellitus, Buerger's disease, Raynaud's disease, coronary artery disease, angina pectoris, and atherosclerosis.

<span class="mw-page-title-main">SDZ SER-082</span> Chemical compound

SDZ SER-082 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors, with good selectivity over other serotonin receptor subtypes and slight preference for 5-HT2C over 5-HT2B. It has been used in animal studies into the behavioural effects of the different 5-HT2 subtypes, and how they influence the effects of other drugs such as cocaine.

<span class="mw-page-title-main">Volinanserin</span> Chemical compound

Volinanserin (INN) is a highly selective 5-HT2A receptor antagonist that is frequently used in scientific research to investigate the function of the 5-HT2A receptor. It was also tested in clinical trials as a potential antipsychotic, antidepressant, and treatment for insomnia but was never marketed.

<span class="mw-page-title-main">SB-215505</span> Chemical compound

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<span class="mw-page-title-main">Glemanserin</span> Chemical compound

Glemanserin (INN) is a drug which acts as a potent and selective 5-HT2A receptor antagonist. The first truly selective 5-HT2A ligand to be discovered, glemanserin resulted in the development of the widely used and even more potent and selective 5-HT2A receptor antagonist volinanserin (MDL-100,907), which is a fluorinated analogue. Though it was largely superseded in scientific research by volinanserin, glemanserin was investigated clinically for the treatment of generalized anxiety disorder. However, it was ultimately found to be ineffective and was not marketed.

<span class="mw-page-title-main">25CN-NBOH</span> Chemical compound

25CN-NBOH is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B. A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to 5-HT2 receptors and autoradiography.

<span class="mw-page-title-main">Pirenperone</span> Chemical compound

Pirenperone (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name; developmental code names R-47456, R-50656) is a serotonin receptor antagonist described as an antipsychotic and tranquilizer which was never marketed. It is a relatively selective antagonist of the serotonin 5-HT2 receptors and has been used in scientific research to study the serotonin system. In the 1980s, the drug was found to block the effects of the lysergic acid diethylamide (LSD) in animals, and along with ketanserin, led to the elucidation of the 5-HT2A receptor as the biological mediator of the effects of serotonergic psychedelics.

<span class="mw-page-title-main">Amesergide</span> Chemical compound

Amesergide is a serotonin receptor antagonist of the ergoline and lysergamide families related to methysergide which was under development by Eli Lilly and Company for the treatment of a variety of conditions including depression, anxiety, schizophrenia, male sexual dysfunction, migraine, and thrombosis but was never marketed. It reached phase II clinical trials for the treatment of depression, erectile dysfunction, and premature ejaculation prior to the discontinuation of its development.

References

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  7. ↑ ATC/DDD Index
  8. ↑ Ketanserin
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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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  15. ↑ 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.
  16. ↑ 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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  23. ↑ 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.
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  28. ↑ CN 106866625,Shiwen R, et al.,issued 2017, assigned to Shanghai Ding Ya Pharmaceutical Chemistry Science And Technology Ltd)
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