WAY-100635


WAY-100635 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-100135.
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.

Human PET studies

In human PET studies WAY-100635 shows high binding in the cerebral cortex, hippocampus, raphe nucleus and amygdaloid nucleus, 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-HT1A receptor binding.
In healthy subjects WAY-100635 binding has been found to decline with age,
— though not all studies have found this relationship.
WhatResultSubjectsRef.
AgeGlobal decrease and particularly in parietal cortex and dorsolateral prefrontal cortex19
AgeNo correlation found61
AgeNo correlation detected25
SexHigher binding in females25
TCI self-transcendence and spiritual acceptance personality traitsPositive correlation in raphe region15 males
Lifetime aggressionNegative correlation25
MADAM binding potential Positive correlation in the raphe nuclei and hippocampus12 males
Genetic variationResultSubjectsRef.
HTR1A.C>G polymorphismNo difference found35
SERT.5-HTTLPR polymorphismLower binding in "all brain regions" for SS or SL genotypes compared to LL35
DiseaseResultSubjectsRef.
Depressive Reduction in raphe nucleus and mesiotemporal cortex12+8
Major depressive disorder Reduction in "many of the regions examined"25+18
Panic disorder in treated and untreated patientsReducing in binding in raphe in both treated and untreated. Reduced binding in global postsynaptic regions for untreated, while no or little reduction for treated.9+7+19
Alzheimer diseaseDecrease in right medial temporal cortex10+10

Radioligands

Labeled with the radioisotope carbon-11 it is used as a radioligand in positron emission tomography studies to determine neuroreceptor binding in the brain.
WAY-100635 may be labeled in different ways with carbon-11:
As WAY-100635 or WAY-100635, with WAY-100635 regarded as "far superior".
Labeled with tritium WAY-100635 may also be used in autoradiography.
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-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-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, an effect most likely linked to desensitisation and/or downregulation of 5-HT1A receptors. As with other 5-HT1A silent antagonists such as UH-301 and robalzotan, WAY-100635 can also induce a head-twitch response in rodents.