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WAY-100635 is a piperazine
drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
and
research chemical Research chemicals are chemical substances which scientists use 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 ...
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 rec ...
, 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. In light of its
dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...
activity, conclusions drawn from studies that employ WAY-100635 as a selective 5-HT1A antagonist may need to be re-evaluated.


Human PET studies

In human PET studies WAY-100635 shows high binding in the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
,
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
, raphe nucleus and amygdaloid nucleus, while lower in
thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
and
basal ganglia The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...
. 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 Raphe ( ; from ;Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon. revised and augmented throughout by Sir Henry Stuart Jones. with the assistance of. Roderick McKenzie.'' Oxford: Clarendon Press. : raphae or raphes) has several differe ...
brain region correlating with self-transcendence and spiritual acceptance
personality trait In psychology, trait theory (also called dispositional theory) is an approach to the study of human personality. Trait theorists are primarily interested in the measurement of ''traits'', which can be defined as habitual patterns of behavior, thou ...
s. WAY-100635 binding has also been assessed in connection with
clinical depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
, where there has been disagreement about the presence and direction of the 5-HT1A 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 has been alive or something 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 A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is a nuclide that has excess numbers of either neutrons or protons, giving it excess nuclear energy, and making it unstable. This excess energy can be used in one of three ...
carbon-11 Carbon (6C) has 14 known isotopes, from to as well as , of which only and are stable nuclide, stable. The longest-lived radionuclide, radioisotope is , with a half-life of years. This is also the only carbon radioisotope found in nature, as ...
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 metabolic processes, and in other physiological activities including blood flow, r ...
(PET) studies to determine neuroreceptor binding in the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
. WAY-100635 may be labeled in different ways with carbon-11: As arbonyl-11CAY-100635 or -methyl-11CAY-100635, with arbonyl-11CAY-100635 regarded as "far superior". Labeled with
tritium Tritium () or hydrogen-3 (symbol T or H) is a rare and radioactive isotope of hydrogen with a half-life of ~12.33 years. The tritium nucleus (t, sometimes called a ''triton'') contains one proton and two neutrons, whereas the nucleus of the ...
WAY-100635 may also be used in autoradiography. WAY-100635 has higher 5-HT1A affinity than
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, 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonis ...
.


Other actions

WAY-100635 has also been found to increase the analgesic effects of
opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
drugs in a dose-dependent manner, in contrast to 5-HT1A agonists such as
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, 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonis ...
which were found to reduce opioid analgesia. However, since 5-HT1A agonists were also found to reduce opioid-induced respiratory depression and WAY-100635 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 Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...
, an effect most likely linked to desensitisation and/or downregulation of 5-HT1A receptors (i.e. analogous to a 5-HT1A antagonist-like effect). As with other 5-HT1A silent antagonists such as
UH-301 (S)-UH-301 is a drug and research chemical widely used in scientific studies. It acts as a selective 5-HT1A receptor silent antagonist. It is structurally related to 8-OH-DPAT 8-OH-DPAT is a research chemical of the aminotetralin chemical cl ...
and robalzotan, 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


External links

*


References

{{Piperazines Dopamine agonists Piperazines Carboxamides 2-Pyridyl compounds Serotonin receptor antagonists 2-Methoxyphenyl compounds