Chemistry:WAY-100635

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Short description: Chemical compound
WAY-100635
WAY-100,635.png
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC25H34N4O2
Molar mass422.573 g·mol−1
3D model (JSmol)
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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]

Human WAY-100635 binding neuroimaging studies (patients compared to healthy control subjects).
What Result Subjects Ref.
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]

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

  1. ↑ "WAY-100635, a potent and selective 5-hydroxytryptamine1A antagonist, increases serotonergic neuronal activity in behaving cats: comparison with (S)-WAY-100135". The Journal of Pharmacology and Experimental Therapeutics 278 (2): 752–762. August 1996. PMID 8768728. http://jpet.aspetjournals.org/cgi/content/abstract/278/2/752. 
  2. ↑ "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology 188 (2): 244–251. October 2006. doi:10.1007/s00213-006-0490-4. PMID 16915381. 
  3. ↑ "WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activation". Behavioural Pharmacology 20 (1): 114–118. February 2009. doi:10.1097/FBP.0b013e3283242f1a. PMID 19179855. 
  4. ↑ "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. 1996. doi:10.1016/0166-4328(96)00118-0. PMID 8788530. 
  5. ↑ "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology 188 (2): 244–251. October 2006. doi:10.1007/s00213-006-0490-4. PMID 16915381. 
  6. ↑ "Localization of 5-HT1A receptors in the living human brain using [carbonyl-11CWAY-100635: PET with anatomic standardization technique"]. Journal of Nuclear Medicine 40 (1): 102–109. January 1999. PMID 9935065. http://jnm.snmjournals.org/cgi/content/abstract/40/1/102. 
  7. ↑ "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. January 2007. doi:10.1038/sj.jcbfm.9600326. PMID 16685258. 
  8. ↑ 8.0 8.1 "The serotonin system and spiritual experiences". The American Journal of Psychiatry 160 (11): 1965–1969. November 2003. doi:10.1176/appi.ajp.160.11.1965. PMID 14594742. 
  9. ↑ "Serotonin-1A receptor imaging in recurrent depression: replication and literature review". Nuclear Medicine and Biology 34 (7): 865–877. October 2007. doi:10.1016/j.nucmedbio.2007.06.008. PMID 17921037. 
  10. ↑ 10.0 10.1 "Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET". Neuropsychopharmacology 24 (5): 522–530. May 2001. doi:10.1016/S0893-133X(00)00227-X. PMID 11282252. 
  11. ↑ 11.0 11.1 "A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables". NeuroImage 15 (3): 620–632. March 2002. doi:10.1006/nimg.2001.0984. PMID 11848705. 
  12. ↑ 12.0 12.1 12.2 12.3 "Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635". Brain Research 954 (2): 173–182. November 2002. doi:10.1016/S0006-8993(02)03243-2. PMID 12414100. 
  13. ↑ "A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain". Psychopharmacology 195 (3): 425–433. December 2007. doi:10.1007/s00213-007-0928-3. PMID 17874074. 
  14. ↑ 14.0 14.1 "A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans". The Journal of Neuroscience 25 (10): 2586–2590. March 2005. doi:10.1523/JNEUROSCI.3769-04.2005. PMID 15758168. 
  15. ↑ "PET imaging of serotonin 1A receptor binding in depression". Biological Psychiatry 46 (10): 1375–1387. November 1999. doi:10.1016/S0006-3223(99)00189-4. PMID 10578452. 
  16. ↑ "Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment". Archives of General Psychiatry 57 (2): 174–180. February 2000. doi:10.1001/archpsyc.57.2.174. PMID 10665620. 
  17. ↑ "Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study". The British Journal of Psychiatry 193 (3): 229–234. September 2008. doi:10.1192/bjp.bp.107.041186. PMID 18757983. 
  18. ↑ "A positron emission tomography study of 5-hydroxytryptamine-1A receptors in Alzheimer disease". The American Journal of Geriatric Psychiatry 15 (10): 888–898. October 2007. doi:10.1097/JGP.0b013e3180488325. PMID 17567932. 
  19. ↑ "First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635". European Journal of Pharmacology 283 (1–3): R1–R3. September 1995. doi:10.1016/0014-2999(95)00438-Q. PMID 7498295. 
  20. ↑ "Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635". European Journal of Pharmacology 301 (1–3): R5–R7. April 1996. doi:10.1016/0014-2999(96)00079-9. PMID 8773468. 
  21. ↑ "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. December 1994. doi:10.1016/0014-2999(94)90813-3. PMID 7705452. 
  22. ↑ "[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. June 1997. doi:10.1016/S0197-0186(96)00124-6. PMID 9152998. 
  23. ↑ "Role of spinal 5-HT(1A) receptors in morphine analgesia and tolerance in rats". European Journal of Pain 8 (3): 253–261. June 2004. doi:10.1016/j.ejpain.2003.09.002. PMID 15109976. 
  24. ↑ "Role of serotonin 5-HT1A and opioid receptors in the antiallodynic effect of tramadol in the chronic constriction injury model of neuropathic pain in rats". Psychopharmacology 193 (1): 97–105. July 2007. doi:10.1007/s00213-007-0761-8. PMID 17393145. 
  25. ↑ "Reversal of morphine-induced apnea in the anesthetized rat by drugs that activate 5-hydroxytryptamine(1A) receptors". The Journal of Pharmacology and Experimental Therapeutics 292 (2): 704–713. February 2000. PMID 10640309. 
  26. ↑ "Dual, hyperalgesic, and analgesic effects of the high-efficacy 5-hydroxytryptamine 1A (5-HT1A) agonist F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt]: relationship with 5-HT1A receptor occupancy and kinetic parameters". The Journal of Pharmacology and Experimental Therapeutics 312 (3): 1034–1042. March 2005. doi:10.1124/jpet.104.077669. PMID 15528450. 
  27. ↑ "Rapid desensitization of somatodendritic 5-HT1A receptors by chronic administration of the high-efficacy 5-HT1A agonist, F13714: a microdialysis study in the rat". British Journal of Pharmacology 149 (2): 170–178. September 2006. doi:10.1038/sj.bjp.0706859. PMID 16921393. 
  28. ↑ "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. February 2009. doi:10.1016/j.neuropharm.2008.09.004. PMID 18809418. 
  29. ↑ Fox MA, Stein AR, French HT, Murphy DL. Functional interactions between 5-HT2A and presynaptic 5-HT1A receptor-based responses in mice genetically deficient in the serotonin 5-HT transporter (SERT). Br J Pharmacol. 2010 Feb;159(4):879-87. "Functional interactions between 5-HT2A and presynaptic 5-HT1A receptor-based responses in mice genetically deficient in the serotonin 5-HT transporter (SERT)". British Journal of Pharmacology 159 (4): 879–887. February 2010. doi:10.1111/j.1476-5381.2009.00578.x. PMID 20128812. 



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