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.
Human PET studies
In human PET studies WAY-100,635 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-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.
|Age||Global decrease and particularly in parietal cortex and dorsolateral prefrontal cortex||19|||
|Age||No correlation found||61|||
|Age||No correlation detected||25|||
|Sex||Higher binding in females||25|||
|TCI self-transcendence and spiritual acceptance personality traits||Positive correlation in raphe region||15 males|||
|Lifetime aggression||Negative correlation||25|||
|MADAM binding potential (serotonin transporter binding)||Positive correlation in the raphe nuclei and hippocampus||12 males|||
|HTR1A.(-1018)C>G polymorphism||No difference found||35|||
|SERT.5-HTTLPR polymorphism||Lower binding in "all brain regions" for SS or SL genotypes compared to LL||35|||
|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 in treated and untreated patients||Reducing 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 disease||Decrease in right medial temporal cortex||10+10|||
Labeled with the radioisotope carbon-11 it is used as a radioligand 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.
WAY-100,635 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-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).