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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.[1][2][3] It is sometimes referred to as a silent antagonist at the former receptor.[4] 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.[5]

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.[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]

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.[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]

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.[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]

See also

External links

References

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  2. ^ Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (October 2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology. 188 (2): 244–251. doi:10.1007/s00213-006-0490-4. PMID 16915381. S2CID 24194034.
  3. ^ Marona-Lewicka D, Nichols DE (February 2009). "WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activation". Behavioural Pharmacology. 20 (1): 114–118. doi:10.1097/FBP.0b013e3283242f1a. PMID 19179855. S2CID 43332577.
  4. ^ Fletcher A, Forster EA, Bill DJ, Brown G, Cliffe IA, Hartley JE, et al. (1996). "Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HT1A receptor antagonist". Behavioural Brain Research. 73 (1–2): 337–353. doi:10.1016/0166-4328(96)00118-0. PMID 8788530. S2CID 18229202.
  5. ^ Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (October 2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology. 188 (2): 244–251. doi:10.1007/s00213-006-0490-4. PMID 16915381. S2CID 24194034.
  6. ^ Ito H, Halldin C, Farde L (January 1999). "Localization of 5-HT1A receptors in the living human brain using [carbonyl-11C]WAY-100635: PET with anatomic standardization technique". Journal of Nuclear Medicine. 40 (1): 102–109. PMID 9935065.
  7. ^ Hirvonen J, Kajander J, Allonen T, Oikonen V, Någren K, Hietala J (January 2007). "Measurement of serotonin 5-HT1A receptor binding using positron emission tomography and [carbonyl-(11)C]WAY-100635-considerations on the validity of cerebellum as a reference region". Journal of Cerebral Blood Flow and Metabolism. 27 (1): 185–195. doi:10.1038/sj.jcbfm.9600326. PMID 16685258.
  8. ^ a b Borg J, Andrée B, Soderstrom H, Farde L (November 2003). "The serotonin system and spiritual experiences". The American Journal of Psychiatry. 160 (11): 1965–1969. doi:10.1176/appi.ajp.160.11.1965. PMID 14594742. S2CID 5911066.
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  19. ^ Pike VW, McCarron JA, Lammerstma AA, Hume SP, Poole K, Grasby PM, et al. (September 1995). "First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635". European Journal of Pharmacology. 283 (1–3): R1–R3. doi:10.1016/0014-2999(95)00438-Q. PMID 7498295.
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  21. ^ Hume SP, Ashworth S, Opacka-Juffry J, Ahier RG, Lammertsma AA, Pike VW, et al. (December 1994). "Evaluation of [O-methyl-3H]WAY-100635 as an in vivo radioligand for 5-HT1A receptors in rat brain". European Journal of Pharmacology. 271 (2–3): 515–523. doi:10.1016/0014-2999(94)90813-3. PMID 7705452.
  22. ^ Burnet PW, Eastwood SL, Harrison PJ (June 1997). "[3H]WAY-100635 for 5-HT1A receptor autoradiography in human brain: a comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia". Neurochemistry International. 30 (6): 565–574. doi:10.1016/S0197-0186(96)00124-6. PMID 9152998. S2CID 21135585.
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  28. ^ Buritova J, Berrichon G, Cathala C, Colpaert F, Cussac D (February 2009). "Region-specific changes in 5-HT1A agonist-induced Extracellular signal-Regulated Kinases 1/2 phosphorylation in rat brain: a quantitative ELISA study". Neuropharmacology. 56 (2): 350–361. doi:10.1016/j.neuropharm.2008.09.004. PMID 18809418. S2CID 45068116.
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