WAY-100635 is a
piperazine drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
and
research chemical
Research chemicals are chemical substances used by scientists for medical and scientific research purposes. One characteristic of a research chemical is that it is for laboratory research use only; a research chemical is not intended for human o ...
widely used in scientific studies. It was originally believed to act as a selective
5-HT1A receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...
, but subsequent research showed that it also acts as
potent full agonist at the
D4 receptor.
It is sometimes referred to as a
silent antagonist at the former receptor. It is closely related to
WAY-100135
WAY-100135 is a serotonergic drug of the phenylpiperazine family which is used in scientific research. It acts as potency (pharmacology), potent 5-HT1A receptor, 5-HT1A receptor receptor antagonist, antagonist, and was originally believed to be h ...
.
In light of its only recently discovered
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
activity, conclusions drawn from studies that employed WAY-100635 as a selective 5-HT
1A antagonist may need to be re-evaluated.
Human PET studies
In human PET studies WAY-100635 shows high binding in the
cerebral cortex,
hippocampus,
raphe nucleus and
amygdaloid nucleus
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
, while lower in
thalamus and
basal ganglia.
One study described a single case with relatively high binding in the cerebellum.
In relating its binding to subject variables one Swedish study found WAY-100635 binding in
raphe brain region correlating with
self-transcendence and spiritual acceptance
personality traits.
WAY-100635 binding has also been assessed in connection with
clinical depression, where there has been disagreement about the presence and direction of the 5-HT
1A receptor binding.
In healthy subjects WAY-100635 binding has been found to decline with
age
Age or AGE may refer to:
Time and its effects
* Age, the amount of time someone or something has been alive or has existed
** East Asian age reckoning, an Asian system of marking age starting at 1
* Ageing or aging, the process of becoming older ...
,
— though not all studies have found this relationship.
Radioligands
Labeled with the
radioisotope carbon-11 it is used as a
radioligand in
positron emission tomography
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...
(PET) studies to determine
neuroreceptor
A neurotransmitter receptor (also known as a neuroreceptor) is a membrane receptor protein that is activated by a neurotransmitter. Chemicals on the outside of the cell, such as a neurotransmitter, can bump into the cell's membrane, in which th ...
binding in the
brain.
WAY-100635 may be labeled in different ways with carbon-11:
As
11C">arbonyl-11CAY-100635 or
11C">-methyl-11CAY-100635, with
11C">arbonyl-11CAY-100635 regarded as "far superior".
Labeled with
tritium WAY-100635 may also be used in
autoradiography
An autoradiograph is an image on an X-ray film or nuclear emulsion produced by the pattern of decay emissions (e.g., beta particles or gamma rays) from a distribution of a radioactive substance. Alternatively, the autoradiograph is also available ...
.
WAY-100635 has higher 5-HT1A affinity than
8-OH-DPAT.
Other actions
WAY-100635 has also been found to increase the analgesic effects of
opioid drugs in a dose-dependent manner, in contrast to 5-HT
1A agonists such as
8-OH-DPAT which were found to reduce opioid analgesia.
However, since 5-HT
1A agonists were also found to reduce opioid-induced
respiratory depression
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapnia ...
and WAY-100635 was found to block this effect,
it is likely that 5-HT
1A antagonists might worsen this side effect of opioids. Paradoxically, chronic administration of the very high efficacy 5-HT
1A agonist
befiradol results in potent analgesia following an initial period of
hyperalgesia, an effect most likely linked to desensitisation and/or downregulation of 5-HT
1A receptors (i.e. analogous to a 5-HT
1A antagonist-like effect).
As with other 5-HT
1A silent antagonists such as
UH-301 and
robalzotan
Robalzotan (NAD-299, AZD-7371) is a selective antagonist at the 5-HT1A receptor. It was shown to completely reverse the autoreceptor-mediated inhibition of serotonin release induced by the administration of selective serotonin reuptake inhibito ...
, WAY-100635 can also induce a
head-twitch response in rodents.
[Fox MA, Stein AR, French HT, Murphy DL. Functional interactions between 5-HT2A and presynaptic 5-HT1A receptor-based responses in mice genetically deficient in the serotonin 5-HT transporter (SERT). ''Br J Pharmacol''. 2010 Feb;159(4):879-87. ]
See also
*
Binding potential
* Other radioligands for the serotonin system:
**
Altanserin
**
DASB
**
Mefway
Mefway is a serotonin 5-HT1A receptor antagonist used in medical research, usually in the form of mefway ( 18F) as a positron emission tomography (PET) radiotracer.
Chemistry
Mefway is closely related to the research compound WAY-100,635. ...
External links
*
References
{{Piperazines
Dopamine agonists
N-(2-methoxyphenyl)piperazines
Carboxamides
2-Pyridyl compounds
Serotonin receptor antagonists