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.[1][2][3] It is sometimes referred to as a silent antagonist at the former receptor.[4] It is closely related to WAY-100135.
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Formula | C25H34N4O2 |
Molar mass | 422.573 g·mol−1 |
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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.[5]
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.[6] One study described a single case with relatively high binding in the cerebellum.[7]
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.[8] 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.[9] In healthy subjects WAY-100635 binding has been found to decline with age,[10] — though not all studies have found this relationship.[11][12]
What | Result | Subjects | Ref. |
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Age | Global decrease and particularly in parietal cortex and dorsolateral prefrontal cortex | 19 | [10] |
Age | No correlation found | 61 | [11] |
Age | No correlation detected | 25 | [12] |
Sex | Higher binding in females | 25 | [12] |
TCI self-transcendence and spiritual acceptance personality traits | Positive correlation in raphe region | 15 males | [8] |
Lifetime aggression | Negative correlation | 25 | [12] |
MADAM binding potential (serotonin transporter binding) | Positive correlation in the raphe nuclei and hippocampus | 12 males | [13] |
Genetic variation | Result | Subjects | Ref. |
HTR1A.(-1018)C>G polymorphism | No difference found | 35 | [14] |
SERT.5-HTTLPR polymorphism | Lower binding in "all brain regions" for SS or SL genotypes compared to LL | 35 | [14] |
Disease | Result | Subjects | Ref. |
Depressive (with primary, recurrent, familial mood disorders) | Reduction in raphe nucleus and mesiotemporal cortex | 12+8 | [15] |
Major depressive disorder (medicated and unmedicated) | Reduction in "many of the regions examined" | 25+18 | [16] |
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 | [17] |
Alzheimer disease | Decrease in right medial temporal cortex | 10+10 | [18] |
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.[19] 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".[20] Labeled with tritium WAY-100635 may also be used in autoradiography.[21] WAY-100635 has higher 5-HT1A affinity than 8-OH-DPAT.[22]
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.[23][24] However, since 5-HT1A agonists were also found to reduce opioid-induced respiratory depression and WAY-100635 was found to block this effect,[25] 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).[26][27][28] As with other 5-HT1A silent antagonists such as UH-301 and robalzotan, WAY-100635 can also induce a head-twitch response in rodents.[29]