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Trade names | Sufrexal |
Other names | R41468; R-41468; R-41,468 |
AHFS/Drugs.com | International Drug Names |
Routes of administration | Oral |
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Pharmacokinetic data | |
Bioavailability | 50% [1] [2] |
Protein binding | 95.0% (mainly albumin [2] |
Elimination half-life | 10–29 hours [3] [1] [2] |
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ECHA InfoCard | 100.070.598 |
Chemical and physical data | |
Formula | C22H22FN3O3 |
Molar mass | 395.434 g·mol−1 |
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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]
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.
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]
Target | Affinity (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] |
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]
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]
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).
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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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:
Pipamperone, sold under the brand name Dipiperon, is a typical antipsychotic of the butyrophenone family used in the treatment of schizophrenia and as a sleep aid for depression. It is or has been marketed under brand names including Dipiperon, Dipiperal, Piperonil, Piperonyl, and Propitan. Pipamperone was discovered at Janssen Pharmaceutica in 1961, and entered clinical trials in the United States in 1963.
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-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.
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.
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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.
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