WAY-100635
Encyclopedia
WAY-100,635 is a piperazine
drug
and research chemical widely used in scientific studies. It was originally believed to act as a selective 5-HT1A receptor antagonist
, 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-100,135
.
In light of its only recently discovered dopaminergic
activity, conclusions drawn from studies that employed WAY-100635 as a selective 5-HT1A antagonist may need to be re-evaluated.
, hippocampus
, raphe nucleus and amygdaloid nucleus, while lower in thalamus
and basal ganglia
.
One study described a case with relatively high binding in the cerebellum.
In relating its binding to subject variables one Swedish study found WAY-100,635 binding in raphe
brain region correlating with self-transcendence and spiritual acceptance personality traits.
WAY-100,635 binding has also been assessed in connection with clinical depression
, where there has been disagreement about the presence and direction of the 5-HT1A receptor binding.
In healthy subjects WAY-100,635 binding has been found to decline with age,
— though not all studies have found this relationship.
in positron emission tomography
(PET) studies to determine neuroreceptor binding in the brain
.
WAY-100,635 may be labeled in different ways with carbon-11:
As [carbonyl-11C]WAY-100,635 or [O-methyl-11C]WAY-100,635, with [carbonyl-11C]WAY-100635 regarded as "far superior".
Labeled with tritium
WAY-100,635 may also be used in autoradiography.
WAY-100,635 has higher 5-HT1A affinity than 8-OH-DPAT
.
drugs in a dose-dependent manner, in contrast to 5-HT1A agonists such as 8-OH-DPAT
which were found to reduce opioid analgesia. However since 5-HT1A agonists were also found to reduce opioid-induced respiratory depression and WAY-100,635 was found to block this effect, it is likely that 5-HT1A antagonists might worsen this side effect of opioids. Paradoxically, chronic administration of the very high efficacy 5-HT1A agonist befiradol
results in potent analgesia following an initial period of hyperalgesia
, an effect most likely linked to desensitisation and/or downregulation of 5-HT1A receptors (i.e. analogous to a 5-HT1A antagonist-like effect).
Piperazine
Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
and research chemical widely used in scientific studies. It was originally believed to act as a selective 5-HT1A receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, 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-100,135
WAY-100,135
WAY-100,135 is a piperazine drug and research chemical used in scientific studies. It was originally believed to act as a selective 5-HT1A receptor antagonist, but subsequent research demonstrated that it also acts as a partial agonist at the 5-HT1B and 5-HT1D receptors....
.
In light of its only recently discovered dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
activity, conclusions drawn from studies that employed WAY-100635 as a selective 5-HT1A antagonist may need to be re-evaluated.
Human PET studies
In human PET studies WAY-100,635 shows high binding in the cerebral cortexCerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, raphe nucleus and amygdaloid nucleus, while lower in thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
and basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
.
One study described a case with relatively high binding in the cerebellum.
In relating its binding to subject variables one Swedish study found WAY-100,635 binding in raphe
Raphe
Raphe has several different meanings in science. Pronounced .In botany and planktology it is commonly used when describing a seam or ridge on diatoms or seeds....
brain region correlating with self-transcendence and spiritual acceptance personality traits.
WAY-100,635 binding has also been assessed in connection with clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, where there has been disagreement about the presence and direction of the 5-HT1A receptor binding.
In healthy subjects WAY-100,635 binding has been found to decline with age,
— though not all studies have found this relationship.
| What | Result | Subjects | Ref. |
|---|---|---|---|
| Age | Global decrease and particularly in parietal cortex and dorsolateral prefrontal cortex Dorsolateral prefrontal cortex The dorsolateral prefrontal cortex , according to a more restricted definition, is roughly equivalent to Brodmann areas 9 and 46. According to a broader definition DL-PFC consists of the lateral portions of Brodmann areas 9 – 12, of areas 45, 46, and the superior part of area 47. These regions... |
19 | |
| Age | No correlation found | 61 | |
| Age | No correlation detected | 25 | |
| Sex Sex In biology, sex is a process of combining and mixing genetic traits, often resulting in the specialization of organisms into a male or female variety . Sexual reproduction involves combining specialized cells to form offspring that inherit traits from both parents... |
Higher binding in females | 25 | |
| TCI Temperament and Character Inventory Temperament and Character Inventory is an inventory for personality traits devised by Cloninger et al.It is closely related to and an outgrowth of Tridimensional Personality Questionnaire ,... self-transcendence and spiritual acceptance personality traits |
Positive correlation in raphe region | 15 males | |
| Lifetime aggression Aggression In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of... |
Negative correlation | 25 | |
| MADAM Madam Madam, or madame, is a polite title used for women which, in English, is the equivalent of Mrs. or Ms., and is often found abbreviated as "ma'am", and less frequently as "ma'm". It is derived from the French madame, which means "my lady", the feminine form of lord; the plural of ma dame in this... binding potential Binding potential In pharmacokinetics and receptor-ligand kinetics the binding potential is a combined measure of the density of "available" neuroreceptors and the affinity of a drug to that neuroreceptor.- Description :Consider a ligand receptor binding system... (serotonin transporter Serotonin transporter The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it... binding) |
Positive correlation in the raphe nuclei Raphe nuclei The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain... and hippocampus Hippocampus The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in... |
12 males | |
| Genetic variation | Result | Subjects | Ref. |
| HTR1A.(-1018)C>G Rs6295 rs6295, also called CG, is a gene variation—a single nucleotide polymorphism —in the HTR1A gene. It is one of the most investigated SNPs of its gene... polymorphism Polymorphism (biology) Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph... |
No difference found | 35 | |
| SERT Serotonin transporter The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it... .5-HTTLPR 5-HTTLPR 5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.Since the polymorphism was identified in the middle of the 1990s,... polymorphism |
Lower binding in "all brain regions" for SS or SL genotypes compared to LL | 35 | |
| Disease | Result | Subjects | Ref. |
| Depressive (with primary, recurrent, familial mood disorders) | Reduction in raphe nucleus and mesiotemporal cortex | 12+8 | |
| Major depressive disorder (medicated and unmedicated) | Reduction in "many of the regions examined" | 25+18 | |
| Panic disorder Panic disorder Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks... in treated and untreated patients |
Reducing in binding in raphe Raphe Raphe has several different meanings in science. Pronounced .In botany and planktology it is commonly used when describing a seam or ridge on diatoms or seeds.... in both treated and untreated. Reduced binding in global postsynaptic regions for untreated, while no or little reduction for treated. |
9+7+19 | |
| Alzheimer disease | Decrease in right medial temporal cortex | 10+10 |
Radioligands
Labeled with the radioisotope carbon-11 it is used as a radioligandRadioligand
A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
in positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET) studies to determine neuroreceptor binding in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
.
WAY-100,635 may be labeled in different ways with carbon-11:
As [carbonyl-11C]WAY-100,635 or [O-methyl-11C]WAY-100,635, with [carbonyl-11C]WAY-100635 regarded as "far superior".
Labeled with tritium
Tritium
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...
WAY-100,635 may also be used in autoradiography.
WAY-100,635 has higher 5-HT1A affinity than 8-OH-DPAT
8-OH-DPAT
8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor...
.
Other actions
WAY-100,635 has also been found to increase the analgesic effects of opioidOpioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
drugs in a dose-dependent manner, in contrast to 5-HT1A agonists such as 8-OH-DPAT
8-OH-DPAT
8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor...
which were found to reduce opioid analgesia. However since 5-HT1A agonists were also found to reduce opioid-induced respiratory depression and WAY-100,635 was found to block this effect, it is likely that 5-HT1A antagonists might worsen this side effect of opioids. Paradoxically, chronic administration of the very high efficacy 5-HT1A agonist befiradol
Befiradol
Befiradol is a very potent and highly selective 5-HT1A receptor full agonist. It has powerful analgesic and antiallodynic effects comparable to those of high doses of opioid painkillers, but with fewer and less prominent side effects, as well as little or no development of tolerance with repeated...
results in potent analgesia following an initial period of hyperalgesia
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
, an effect most likely linked to desensitisation and/or downregulation of 5-HT1A receptors (i.e. analogous to a 5-HT1A antagonist-like effect).
See also
- Binding potentialBinding potentialIn pharmacokinetics and receptor-ligand kinetics the binding potential is a combined measure of the density of "available" neuroreceptors and the affinity of a drug to that neuroreceptor.- Description :Consider a ligand receptor binding system...
- Other radioligands for the serotonin system:
- AltanserinAltanserinAltanserin is a compound that binds to the 5-HT2A receptor .It is a yellowish solid.Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography studies of the brain, i.e., studies of the serotonin-2A neuroreceptors.Besides human neuroimaging studies altanserin...
- DASBDASBDASB is a compound that binds to the serotonin transporter.Labeled with carbon-11 — a radioactive isotope — it has been used as a radioligand in neuroimaging with positron emission tomography since around year 2000....
- Altanserin