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 dopaminergic 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, 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.
| What | Result | Subjects | Ref. |
|---|---|---|---|
| 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 | |
| Genetic variation | Result | Subjects | Ref. |
| 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 | |
| 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 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's disease | Decrease in right medial temporal cortex | 10+10 |
Radioligands
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-100635 may be labeled in different ways with carbon-11: As [carbonyl-11C]WAY-100635 or [O-methyl-11C]WAY-100635, with [carbonyl-11C]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 (i.e. analogous to a 5-HT1A antagonist-like effect). As with other 5-HT1A silent antagonists such as UH-301, WAY-100635 can also induce a head-twitch response in rodents.
