WAY-100,635

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WAY-100,635
WAY-100,635.png
Systematic (IUPAC) name
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridyl)cyclohexanecarboxamide
Clinical data
Legal status ?
Identifiers
CAS number 146714-97-8 YesY
ATC code ?
PubChem CID 5684
IUPHAR ligand 80
ChemSpider 5482 N
ChEMBL CHEMBL31354 N
Chemical data
Formula C25H34N4O2 
Mol. mass 422.56 g/mol
 N (what is this?)  (verify)

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

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.[5] One study described a single case with relatively high binding in the cerebellum.[6]

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.[7] 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.[8] In healthy subjects WAY-100,635 binding has been found to decline with age,[9] — though not all studies have found this relationship.[10][11]

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 [9]
Age No correlation found 61 [10]
Age No correlation detected 25 [11]
Sex Higher binding in females 25 [11]
TCI self-transcendence and spiritual acceptance personality traits Positive correlation in raphe region 15 males [7]
Lifetime aggression Negative correlation 25 [11]
MADAM binding potential (serotonin transporter binding) Positive correlation in the raphe nuclei and hippocampus 12 males [12]
Genetic variation Result Subjects Ref.
HTR1A.(-1018)C>G polymorphism No difference found 35 [13]
SERT.5-HTTLPR polymorphism Lower binding in "all brain regions" for SS or SL genotypes compared to LL 35 [13]
Disease Result Subjects Ref.
Depressive (with primary, recurrent, familial mood disorders) Reduction in raphe nucleus and mesiotemporal cortex 12+8 [14]
Major depressive disorder (medicated and unmedicated) Reduction in "many of the regions examined" 25+18 [15]
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 [16]
Alzheimer disease Decrease in right medial temporal cortex 10+10 [17]

Radioligands[edit]

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.[18] 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".[19] Labeled with tritium WAY-100,635 may also be used in autoradiography.[20] WAY-100,635 has higher 5-HT1A affinity than 8-OH-DPAT.[21]

Other actions[edit]

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.[22][23] However since 5-HT1A agonists were also found to reduce opioid-induced respiratory depression and WAY-100,635 was found to block this effect,[24] 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).[25][26][27]

See also[edit]

External links[edit]

References[edit]

  1. ^ C. A. Fornal, C. W. Metzler, R. A. Gallegos, S. C. Veasey, A. C. McCreary and B. L. Jacobs (1996). "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. PMID 8768728. 
  2. ^ Benjamin R. Chemel, Bryan L. Roth, Blaine Armbruster, Val J. Watts and David E. Nichols (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. 
  3. ^ Marona-Lewicka D, Nichols DE (2009). "WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activation". Behav Pharmacol 20 (1): 114–8. doi:10.1097/FBP.0b013e3283242f1a. PMID 19179855. 
  4. ^ A. Fletcher, E. A. Forster, D. J. Bill, G. Brown, I. A. Cliffe, J. E. Hartley, D. E. Jones, A. McLenachan, K. J. Stanhope, D. J. Critchley, K. J. Childs, V. C. Middlefell, L. Lanfumey, R. Corradetti, A. M. Laporte, H. Gozlan, M. Hamon & C. T. Dourish (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): 337–333. doi:10.1016/0166-4328(96)00118-0. PMID 8788530. 
  5. ^ Hiroshi Ito, Christer Halldin & Lars Farde (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. 
  6. ^ Jussi Hirvonen, Jaana Kajander, Topias Allonen, Vesa Oikonen, Kjell Nagren & Jarmo Hietala (January 2007). "Measurement of serotonin 5-HT1A receptor binding using positron emission tomography and [carbonyl-11C]WAY-100635—considerations on the validity of cerebellum as a reference region". Journal of Cerebral Blood Flow and Metabolism 27 (1): 185–185. doi:10.1038/sj.jcbfm.9600326. PMID 16685258. 
  7. ^ a b Jacqueline Borg, Bengt Andrée, Henrik Soderstrom, Lars Farde (November 2003). "The Serotonin System and Spiritual Experiences". American Journal of Psychiatry 160 (11): 1965–1969. doi:10.1176/appi.ajp.160.11.1965. PMID 14594742. 
  8. ^ Wayne C. Drevets, Michael E. Thase, Eydie L. Moses-Kolko, Julie Price, Ellen Frank, David J. Kupfer and Chester Mathis (October 2007). "Serotonin-1A receptor imaging in recurrent depression: replication and literature review". Nuclear Medicine and Biology 34 (7): 865–877. doi:10.1016/j.nucmedbio.2007.06.008. PMC 2702715. PMID 17921037. 
  9. ^ a b Johannes Tauscher, N. Paul L. G. Verhoeff, Bruce K. Christensen, Doug Hussey, Jeffrey H. Meyer, Alex Kecojevic, Mahan Javanmard, Siegfried Kasper and Shitij Kapur (May 2001). "Serotonin 5-HT1A Receptor Binding Potential Declines with Age as Measured by [11C]WAY-100635 and PET". Neuropsychopharmacology 24 (5): 522–530. doi:10.1016/S0893-133X(00)00227-X. 
  10. ^ a b Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence AD, Bench CJ, Gunn RN, Cowen P, Grasby PM. (March 2002). "A database of [11C]WAY-100635 binding to 5-HT1A receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables". NeuroImage 15 (3): 620–632. doi:10.1006/nimg.2001.0984. PMID 11848705. 
  11. ^ a b c d R. V. Parsey, M. A. Oquendo, N. R. Simpson, R. T. Ogden, R. Van Heertum, V. Arango V, J. J. Mann (November 2002). "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. doi:10.1016/S0006-8993(02)03243-2. PMID 12414100. 
  12. ^ Johan Lundberg, Jacqueline Borg, Christer Halldin and Lars Farde (December 2007). "A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain". Psychopharmacology 195 (3): 425–433. doi:10.1007/s00213-007-0928-3. 
  13. ^ a b Sean P. David, Naga Venkatesha Murthy, Eugenii A. Rabiner, Marcus R. Munafó, Elaine C. Johnstone, Robyn Jacob, Robert T. Walton & Paul M. Grasby (March 2005). "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. doi:10.1523/JNEUROSCI.3769-04.2005. PMC 1942077. PMID 15758168. 
  14. ^ Wayne C. Drevets, Ellen Frank, Julie C. Price, David J. Kupfer, Daniel Holt, Phil J. Greer, Yiyun Huang, Clara Gautier and Chester Mathis (November 1999). "Pet imaging of serotonin 1A receptor binding in depression". Biological Psychiatry 46 (10): 1375–1387. doi:10.1016/S0006-3223(99)00189-4. PMID 10578452. 
  15. ^ Peter A. Sargent, Karen Husted Kjaer, Christopher J. Bench, Eugenii A. Rabiner, Cristina Messa, Jeff Meyer, Roger N. Gunn, Paul M. Grasby, Philip J. Cowen (February 2000). "Brain Serotonin1A Receptor Binding Measured by Positron Emission Tomography With [11C]WAY-100635. Effects of Depression and Antidepressant Treatment". Archieves of General Psychiatry 57 (2): 174–180. doi:10.1001/archpsyc.57.2.174. 
  16. ^ Jon R. Nash, Peter A. Sargent, Eugenii A. Rabiner, Sean D. Hood, Paul M. Grasby & David J. Nutt (2008). "Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study". The British Journal of Psychiatry 193 (3): 229–234. doi:10.1192/bjp.bp.107.041186. PMID 18757983. 
  17. ^ Krista L. Lanctôt, Doug F. Hussey, Nathan Herrmann, , Sandra E. Black, Pablo M. Rusjan, Alan A. Wilson, Sylvain Houle, Nicole Kozloff, Nicholaas Paul L.G. Verhoeff, and Shitij Kapur (October 2007). "A positron emission tomography study of 5-hydroxytryptamine-1A receptors in Alzheimer disease". American Journal of Geriatric Psychiatry 15 (10): 888–898. doi:10.1097/JGP.0b013e3180488325. PMID 17567932. 
  18. ^ Victor W. Pike, Julie A. McCarron, Adriaan A. Lammerstma, Susan P. Hume, Keith Poole, Paul M. Grasby, Andrea Malizia, Ian A. Cliffe, Allan Fletcher & Christopher J. Bench (September 1995). "First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635". European Journal of Pharmacology 283 (s 1-3): R1–R3. doi:10.1016/0014-2999(95)00438-Q. PMID 7498295. 
  19. ^ Victor W. Pike, Julie A. McCarron, Adriaan A. Lammertsma, Safiye Osman, Susan P. Hume, Peter A. Sargent, Christopher J. Bench, Ian A. Cliffe, Alan Fletcher and Paul M. Grasby (April 1996). "Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11C]WAY-100635". European Journal of Pharmacology 301 (1-3): R5–R7. doi:10.1016/0014-2999(96)00079-9. 
  20. ^ Susan P. Hume, Sharon Ashworth, Jolanta Opacka-Juffry, Randal G. Ahier, Adriaan A. Lammertsma, Victor W. Pike, Ian A. Cliffe, Allan Fletcher and Alan C. White (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. 
  21. ^ P. W. J. Burnet, S. L. Eastwood & P. J. Harrison (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. 
  22. ^ Bardin L, Colpaert FC (June 2004). "Role of spinal 5-HT(1A) receptors in morphine analgesia and tolerance in rats". European Journal of Pain 8 (3): 253–61. doi:10.1016/j.ejpain.2003.09.002. PMID 15109976. 
  23. ^ Berrocoso E, De Benito MD, Mico JA (July 2007). "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. doi:10.1007/s00213-007-0761-8. PMID 17393145. 
  24. ^ Sahibzada N, Ferreira M, Wasserman AM, Taveira-DaSilva AM, Gillis RA (February 2000). "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): 704–13. PMID 10640309. 
  25. ^ Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, Sautel F, Koek W, Colpaert FC (March 2005). "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): 1034–42. doi:10.1124/jpet.104.077669. PMID 15528450. 
  26. ^ Assié MB, Lomenech H, Ravailhe V, Faucillon V, Newman-Tancredi A (September 2006). "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): 170–8. doi:10.1038/sj.bjp.0706859. PMC 2013794. PMID 16921393. 
  27. ^ 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): 350–61. doi:10.1016/j.neuropharm.2008.09.004. PMID 18809418.