Ketanserin
Clinical data | |
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Trade names | Sufrexal |
Other names | R-41468; R41468; R-41,468; KJK-945; R-49945; R49945 |
AHFS/Drugs.com | International Drug Names |
Routes of administration | Oral |
ATC code | |
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Pharmacokinetic data | |
Bioavailability | 50%[1][2] |
Protein binding | 95% (mainly albumin[2][3] |
Metabolism | Extensive[3] |
Metabolites | • Ketanserin-ol[3] |
Elimination half-life | 10–29 hours[4][1][2] |
Excretion | Urine; 2% unchanged[3] |
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CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.070.598 |
Chemical and physical data | |
Formula | C22H22FN3O3 |
Molar mass | 395.434 g·mol−1 |
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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
Medical uses
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
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
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
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
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
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 INN , USAN , BAN .[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
References
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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.
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