WAY-100635 is a

piperazine Piperazine () is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste. The piperazines are a broad ...

drug and research chemical widely used in scientific studies. It was originally believed to act as a selective 5-HT_1A 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 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 recep ...

at the former receptor. It is closely related to WAY-100135. In light of its only recently discovered dopaminergic 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 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. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

, raphe nucleus and amygdaloid nucleus, while lower in

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

and

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...

. 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 Greek ῥαφή, "seam"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.) has several diffe ...

brain region correlating with

self-transcendence Self-transcendence is a personality trait that involves the expansion of personal boundaries, including, potentially, experiencing spiritual ideas such as considering oneself an integral part of the universe. Several psychologists, including Vikto ...

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 behaviour, tho ...

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-HT_1A receptor binding. In healthy subjects WAY-100635 binding has been found to decline with age, — 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 nuclear energy, making it unstable. This excess energy can be used in one of three ways: emitted from the nucleus as gamma radiation; transferr ...

carbon-11 it is used as a

radioligand A radioligand is a radioactive biochemical substance (in particular, a ligand (biochemistry), ligand that is radioactive tracer, radiolabeled) that is used for diagnosis or for research-oriented study of the receptor (biochemistry), receptor system ...

in positron emission tomography (PET) studies to determine neuroreceptor binding in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

. 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 , ) or hydrogen-3 (symbol T or H) is a rare and radioactive isotope of hydrogen with half-life about 12 years. The nucleus of tritium (t, sometimes called a ''triton'') contains one proton and two neutrons, whereas the nucleus of ...

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. It was one of the first major 5-HT1A receptor full agonists to be discove ...

Other actions

WAY-100635 has also been found to increase the analgesic effects of

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

drugs in a dose-dependent manner, in contrast to 5-HT_1A agonists such as

which were found to reduce opioid analgesia. However, since 5-HT_1A agonists were also found to reduce opioid-induced respiratory depression 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 Befiradol (F-13,640; NLX-112) is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist. Pharmacology In recombinant cell lines expressing human 5-HT1A ...

results in potent analgesia following an initial period of

hyperalgesia Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...

, 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 (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. UH-301 was found to produce a head-twitch response in mice which is ...

and robalzotan, WAY-100635 can also induce a

head-twitch response The head-twitch response (HTR) is a rapid side-to-side head movement that occurs in mice and rats after the serotonin 5-HT2A receptor is activated. The prefrontal cortex may be the neuroanatomical locus mediating the HTR. Many serotonergic hallucino ...

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.

External links

References

{{Piperazines Dopamine agonists N-(2-methoxyphenyl)piperazines Carboxamides 2-Pyridyl compounds Serotonin receptor antagonists

Human PET studies

Radioligands

Other actions

See also

External links

References