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| Trade names | Sufrexal, Serefrex |
| Other names | R-41468; R41468; R-41,468; KJK-945; R-49945; R49945 |
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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Bioavailability | 50%[1][2] |
| Protein binding | 95% (mainlyalbumin[2][3] |
| Metabolism | Extensive[3] |
| Metabolites | • Ketanserin-ol[3] |
| Eliminationhalf-life | 10–29 hours[4][1][2] |
| Excretion | Urine; 2% unchanged[3] |
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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, sold under the brand nameSufrexal, is anantihypertensive agent which is used to treatarterial hypertension andvasospastic disorders.[5][6][3] It is also used inscientific research as anantiserotonergicagent in the study of theserotonin system; specifically, the5-HT2 receptor family.[7] The drug is takenby mouth.[6][3]
Side effects of ketanserin includedizziness,tiredness,edema,dry mouth,weight gain, andQT interval prolongation.[6] Ketanserin acts as aselectiveantagonist of theserotonin5-HT2A,α1-adrenergic, andhistamineH1 receptors.[6][8][9] It also shows loweraffinity for various othertargets.[9]
Ketanserin was discovered atJanssen 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 theUnited States[1] and is mostly no longer marketed throughout the rest of the world.[12][13]
Ketanserin is classified as anantihypertensive by theWorld Health Organization[14] and theNational Institute of Health.[15]
It has been used to reverse pulmonary hypertension caused byprotamine (which in turn was administered to reverse the effects ofheparin overdose).[16]
The reduction in hypertension is not associated with reflex tachycardia.[17]
It has been used in cardiac surgery.[18]
A 2000Cochrane Review found that, compared to placebo, ketanserin did not provide significant relief for people suffering fromRaynaud's phenomenon attacks in the setting ofprogressive 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 atopical gel formulation for treating wounds, burns, ulcers, and anal fissures. Its action is through the acceleration of epithelialization.
Withtritium (3H)radioactively labeled ketanserin is used as aradioligand for serotonin 5-HT2 receptors, e.g. inreceptor binding assays andautoradiography.[20] This radio-labeling has enabled the study of serotonin5-HT2A receptordistribution in thehuman brain.[21]
An autoradiography study of the humancerebellum has found an increasing binding of3H-ketanserin withage (from below 50femtomol 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 theirhomogenate binding study.
Ketanserin has also been used withcarbon (11C)radioactively labeled NNC112 in order to image corticalD1 receptors without contamination by 5-HT2 receptors.[23]
Increasing research into the use ofpsychedelics asantidepressants has seen ketanserin used to bothblock the hallucinogenic experience, and to disentangle the specific cognitive effects of 5-HT2A activation.[24] Ketanserin has been found to block the psychedelic effects ofpsilocybin,[25]lysergic acid diethylamide (LSD),[26][27]mescaline,[28] andayahuasca (dimethyltryptamine)[29] in clinical studies.[24][30]
| Target | Affinity (Ki) | Ref(s) |
|---|---|---|
| 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] |
| α1A | 6.3 nM | [32] |
| α1B | 6.3 nM | [32] |
| α1D | 16 nM | [32] |
| α2A | 372 nM (HT29) | [31] |
| α2B | 199 nM | [31] |
| α2C | 159 nM (opossum) | [31] |
| H1 | 1.79 nM | [31] |
| DAT | >10,000 nM | [31] |
| VMAT1 | 1,600 nM | [32] |
| VMAT2 | 22–540 nM | [32][9] |
Ketanserin is a high-affinity non-selectiveantagonist of5-HT2 receptors in rodents.[31][35][33][36] In addition to the 5-HT2 receptors, ketanserin is also a high affinity antagonist for theH1 receptor.[37] It has also been found to block thevesicular monoamine transporter 2 (VMAT2).[38][39]
Occupancy of the serotonin 5-HT2A receptor by ketanserin in humans has been studied.[40]
Thebioavailability of ketanserin is 50%.[1][2] Theplasma protein binding of ketanserin is 95.0% and it is mainly bound toalbumin.[2] Theelimination half-life of ketanserin is 10 to 29 hours.[4][1]
Ketanserin is a piperidinylethylquinazoline derivative.[41][42]
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).
Analogues of ketanserin includealtanserin,ocaperidone,paliperidone,pelanserin,pirenperone,risperidone,ritanserin, andsetoperone, among others.[41][12]
Ketanserin was first described in thescientific literature by 1980.[41][48][49][50]
Ketanserin is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name.[12][42][41] It is also known by its major brand namesSufrexal andSerefrex and by its former developmental code namesR-41468,KJK-945, andR-49945.[12][42][41]
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.
Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
