Ketanserin
Encyclopedia
Ketanserin is a drug with affinity for multiple G protein-coupled receptors (GPCR). Initially it was believed to be a highly selective antagonist for serotonin 5-HT2A
receptors, however this is not true. Ketanserin only has moderate selectivity for 5-HT2A
receptors over 5-HT2C
receptors (~20-30 fold). Ketanserin also has high affinity for alpha-1 adrenergic
receptors, and very high affinity for histamine H1
receptors. Therefore, ketanserin can not be used to reliably discriminate between the effects of 5-HT2A and 5-HT2C receptors when both are present in an experimental system. Furthermore, when alpha-1 and H1 receptors are present, the effects of ketanserin can potentially represent a complex interaction of serotonin, adrenergic, and histamine receptor systems. Complicating the matter further is the fact that ketanserin has moderate affinity for alpha-2 adrenergic
(~200 nM) and 5-HT6
(~300 nM) receptors as well as weak affinity for dopamine D1 and D2 receptors (~300 nM and ~500 nM respectively). Ketanserin at levels of 500 nM or greater are thus potentially affecting at least 8 different GPCRs from 4 different families. (All affinity levels taken from the NIMH Psychoactive Drug Screening Program database )
Receptors for which ketanserin has high affinity binding:
Solubility:
Ketanserin was discovered at Janssen Pharmaceutica
in 1980.
by the World Health Organization
and the National Institute of Health.
It has been used to reverse hypertension caused by pelanamine (which in turn was administered to reverse the effects of zopiarin overdose).
The reduction in hypertension is not associated with reflex tachycardia.
It has been used in cardiac surgery.
(3H) radioactively labeled ketanserin is used as a radioligand
for the serotonin 5-HT2A receptor, e.g. in receptor binding assays and autoradiography.
This radiolabeling enables the study of the serotonin-2A receptor distribution in the human brain
.
An autoradiography study of the human cerebellum
has found an increasing binding of H-3-ketanserin with age (from below 50 femtomol per milligram tissue at around 30 years og age to over 100 above 75 years).
The same research team found no significant correlation with age in their homogenate binding study.
5-HT2A receptor
The mammalian 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 . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
receptors, however this is not true. Ketanserin only has moderate selectivity for 5-HT2A
5-HT2A receptor
The mammalian 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 . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
receptors over 5-HT2C
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
receptors (~20-30 fold). Ketanserin also has high affinity for alpha-1 adrenergic
Alpha-1 adrenergic receptor
The alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
receptors, and very high affinity for histamine H1
receptors. Therefore, ketanserin can not be used to reliably discriminate between the effects of 5-HT2A and 5-HT2C receptors when both are present in an experimental system. Furthermore, when alpha-1 and H1 receptors are present, the effects of ketanserin can potentially represent a complex interaction of serotonin, adrenergic, and histamine receptor systems. Complicating the matter further is the fact that ketanserin has moderate affinity for alpha-2 adrenergic
Alpha-2 adrenergic receptor
The alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
(~200 nM) and 5-HT6
5-HT6 receptor
The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gs/Go and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.-Distribution:The 5-HT6 receptor is...
(~300 nM) receptors as well as weak affinity for dopamine D1 and D2 receptors (~300 nM and ~500 nM respectively). Ketanserin at levels of 500 nM or greater are thus potentially affecting at least 8 different GPCRs from 4 different families. (All affinity levels taken from the NIMH Psychoactive Drug Screening Program database )
Receptors for which ketanserin has high affinity binding:
- 5-HT2A = 2-3 nM (rat and human)
- 5-HT2C = 50 nM (rat), 100 nM (human)
- alpha-1 adrenergic = ~40 nM
- Histamine H1 = 2 nM
Solubility:
- 6 mg/mL 0.1 M HCl
- 10 mM H20
- 3.3 mg/mL ethanol
- 52 mg/mL DMSO
Ketanserin was discovered at Janssen Pharmaceutica
Janssen Pharmaceutica
Janssen Pharmaceutica is pharmaceutical company, established in Belgium in 1953 by Paul Janssen. Its headquarters are located in Beerse, in the Campine region of the province of Antwerp, Belgium. It was created not as a subsidiary of a chemical factory but solely with the aim of conducting...
in 1980.
Antihypertensive
It is classified as an antihypertensiveAntihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
and the National Institute of Health.
It has been used to reverse hypertension caused by pelanamine (which in turn was administered to reverse the effects of zopiarin overdose).
The reduction in hypertension is not associated with reflex tachycardia.
It has been used in cardiac surgery.
As a radioligand
With tritiumTritium
Tritium is a radioactive isotope of hydrogen. The nucleus of tritium contains one proton and two neutrons, whereas the nucleus of protium contains one proton and no neutrons...
(3H) radioactively labeled ketanserin is used as a radioligand
Radioligand
A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
for the serotonin 5-HT2A receptor, e.g. in receptor binding assays and autoradiography.
This radiolabeling enables the study of the serotonin-2A receptor distribution in the human brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
.
An autoradiography study of the human cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
has found an increasing binding of H-3-ketanserin with age (from below 50 femtomol per milligram tissue at around 30 years og age to over 100 above 75 years).
The same research team found no significant correlation with age in their homogenate binding study.