# Ketanserin

Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospastic disorders. It is also used in scientific research as an antiserotonergic agent in the study of the serotonin system; specifically, the 5-HT$_2$ receptor family. The drug is taken by mouth.
Side effects of ketanserin include dizziness, tiredness, edema, dry mouth, weight gain, and QT interval prolongation. Ketanserin acts as a selective antagonist of the serotonin 5-HT$_{2A}$, α$_1$-adrenergic, and histamine H$_1$ receptors. It also shows lower affinity for various other targets.
Ketanserin was discovered at Janssen Pharmaceutica in 1980. It was the first serotonin 5-HT$_{2A}$ receptor antagonist to be discovered that showed selectivity over other serotonin receptors. The drug is not available in the United States and is mostly no longer marketed throughout the rest of the world.

## Uses
### Medical uses

Ketanserin is classified as an antihypertensive by the World Health Organization and the National Institute of Health.
It has been used to reverse pulmonary hypertension caused by protamine (which in turn was administered to reverse the effects of heparin overdose).
The reduction in hypertension is not associated with reflex tachycardia.
It has been used in cardiac surgery.
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.
Ketanserin is a selective 5-HT$_{2A}$ 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 ($^3$H) radioactively labeled ketanserin is used as a radioligand for serotonin 5-HT$_2$ receptors, e.g. in receptor binding assays and autoradiography. This radio-labeling has enabled the study of serotonin 5-HT$_{2A}$ receptor distribution in the human brain.
An autoradiography study of the human cerebellum has found an increasing binding of $^3$H-ketanserin with age (from below 50 femtomol per milligram tissue at around 30 years of age to over 100 above 75 years). The same research team found no significant correlation with age in their homogenate binding study.
Ketanserin has also been used with carbon ($^{11}$C) radioactively labeled NNC112 in order to image cortical D$_1$ receptors without contamination by 5-HT$_2$ receptors.
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-HT$_{2A}$ activation. Ketanserin has been found to block the psychedelic effects of psilocybin, lysergic acid diethylamide (LSD), mescaline, and ayahuasca (dimethyltryptamine) in clinical studies.

## Pharmacology

Human molecular targets of ketanserin :
| Target | Affinity (K$_i$) |
| α$_{1A}$-adrenergic | 6.3 nM |
| α$_{1B}$-adrenergic | 6.3 nM |
| α$_{1D}$-adrenergic | 16 nM |
| α$_{2A}$-adrenergic | 372 nM (HT29) |
| α$_{2B}$-adrenergic | 199 nM |
| α$_{2C}$-adrenergic | 159 nM (opossum) |
| 5-HT$_{1A}$ | 1,044–>10,000 nM |
| 5-HT$_{1B}$ | 2,515–6,300 nM |
| 5-HT$_{1D}$ | 32–>10,000 nM |
| 5-HT$_{1E}$ | >10,000 nM |
| 5-HT$_{1F}$ | 1.25–>10,000 nM |
| 5-HT$_{2A}$ | 0.20–9.8 nM |
| 5-HT$_{2B}$ | 200–3,236 nM |
| 5-HT$_{2C}$ | 17–186 nM |
| 5-HT$_3$ | >10,000 nM (rodent) |
| 5-HT$_{4L}$ | 1,000 nM (rat) |
| 5-HT$_{5A}$ | 20,000 nM |
| 5-HT$_{5B}$ | 1,000–1,585 nM (rodent) |
| 5-HT$_6$ | 2,800 nM |
| 5-HT$_7$ | 320–1,334 nM |
| D$_1$ | 190–464 nM |
| D$_2$ | >10,000 nM |
| D$_3$ | ? |
| D$_4$ | 148 nM (canine) |
| D$_5$ | 2,500 nM |
| H$_1$ | 1.79 nM |
| DAT | >10,000 nM |
| VMAT1 | 1,600 nM |
| VMAT2 | 22–540 nM |

### Pharmacodynamics

Ketanserin is a high-affinity non-selective antagonist of 5-HT$_2$ receptors in rodents, In addition to the 5-HT$_2$ receptors, ketanserin is also a high affinity antagonist for the H$_1$ receptor. It has also been found to block the vesicular monoamine transporter 2 (VMAT2).
Occupancy of the serotonin 5-HT$_{2A}$ receptor by ketanserin in humans has been studied.

### Pharmacokinetics

The bioavailability of ketanserin is 50%. The plasma protein binding of ketanserin is 95.0% and it is mainly bound to albumin. The elimination half-life of ketanserin is 10 to 29 hours.

## 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 INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name. It is also known by its major brand name Sufrexal and by its former developmental code names R-41468, KJK-945, and R-49945.