WAY-100635

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WAY-100635
WAY-100,635.png
Identifiers
  • N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C25H34N4O2
Molar mass 422.573 g·mol−1
3D model (JSmol)
  • COC1=CC=CC=C1N2CCN(CC2)CCN(C3=CC=CC=N3)C(=O)C4CCCCC4
  • InChI=1S/C25H34N4O2/c1-31-23-12-6-5-11-22(23)28-18-15-27(16-19-28)17-20-29(24-13-7-8-14-26-24)25(30)21-9-3-2-4-10-21/h5-8,11-14,21H,2-4,9-10,15-20H2,1H3 X mark.svgN
  • Key:SBPRIAGPYFYCRT-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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.

Contents

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).
WhatResultSubjectsRef.
Age Global decrease and particularly in parietal cortex and dorsolateral prefrontal cortex 19 [10]
Age No correlation found61 [11]
Age No correlation detected25 [12]
Sex Higher binding in females25 [12]
TCI self-transcendence and spiritual acceptance personality traits Positive correlation in raphe region15 males [8]
Lifetime aggression Negative correlation25 [12]
MADAM binding potential (serotonin transporter binding)Positive correlation in the raphe nuclei and hippocampus 12 males [13]
Genetic variationResultSubjectsRef.
HTR1A.(-1018)C>G polymorphism No difference found35 [14]
SERT.5-HTTLPR polymorphismLower binding in "all brain regions" for SS or SL genotypes compared to LL35 [14]
DiseaseResultSubjectsRef.
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 patientsReducing 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

Related Research Articles

A radioligand is a radioactive biochemical substance, in particular, a ligand that is radiolabeled. Radioligands are used for diagnosis or for research-oriented study of the receptor systems of the body, and for anti-cancer radioligand therapy.

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones.

5-HT<sub>4</sub> receptor Protein-coding gene in the species Homo sapiens

5-Hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.

The 5-HT1 receptors are a subfamily of the 5-HT serotonin receptors that bind to the endogenous neurotransmitter serotonin (also known as 5-hydroxytryptamine, or 5-HT). The 5-HT1 subfamily consists of five G protein-coupled receptors (GPCRs) that share 40% to 63% overall sequence homology, including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. Receptors of the 5-HT1 type, specifically, the 5-HT1A and 5-HT1D receptor subtypes, are present on the cell bodies. Receptors of the 5-HT1 type, specifically, the 5-HT1B and 5-HT1D receptor subtypes, are also present on the nerve terminals. These receptors are broadly distributed throughout the brain and are recognized to play a significant part in regulating synaptic levels of 5-HT.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarisation and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

5-HT<sub>1B</sub> receptor Mammalian protein found in Homo sapiens

5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.

5-HT<sub>1F</sub> receptor Protein-coding gene in the species Homo sapiens

5-hydroxytryptamine (serotonin) receptor 1F, also known as HTR1F is a 5-HT1 receptor protein and also denotes the human gene encoding it.

5-HT<sub>5A</sub> receptor Protein-coding gene in the species Homo sapiens

5-Hydroxytryptamine (serotonin) receptor 5A, also known as HTR5A, is a protein that in humans is encoded by the HTR5A gene. Agonists and antagonists for 5-HT receptors, as well as serotonin uptake inhibitors, present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions, and 5-HT receptors are also associated with neural changes.

5-HT<sub>6</sub> receptor Protein-coding gene in the species Homo sapiens

The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.

5-HT<sub>7</sub> receptor Protein-coding gene in the species Homo sapiens

The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) The 5-HT7 receptor is coupled to Gs (stimulates the production of the intracellular signaling molecule cAMP) and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. This receptor has been a drug development target for the treatment of several clinical disorders. The 5-HT7 receptor is encoded by the HTR7 gene, which in humans is transcribed into 3 different splice variants.

<span class="mw-page-title-main">Altanserin</span> Chemical compound

Altanserin is a compound that binds to the 5-HT2A receptor. Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography (PET) studies of the brain, i.e., studies of the 5-HT2A neuroreceptors. Besides human neuroimaging studies altanserin has also been used in the study of rats.

rs6295, also called C(-1019)G, is a gene variation—a single nucleotide polymorphism (SNP)—in the HTR1A gene. It is one of the most investigated SNPs of its gene. The C-allele is the most prevalent with 0.675 against the G-allele with 0.325 among Caucasian.

<span class="mw-page-title-main">WAY-100135</span> Chemical compound

WAY-100135 is a serotonergic drug of the phenylpiperazine family which is used in scientific research. It acts as potent 5-HT1A receptor antagonist, and was originally believed to be highly selective, but further studies have demonstrated that it also acts as a partial agonist of the 5-HT1D receptor (pKi = 7.58; virtually the same affinity for 5-HT1A), and to a much lesser extent, of the 5-HT1B receptor (pKi = 5.82). These findings may have prompted the development of the related compound WAY-100635, another purportedly selective and even more potent 5-HT1A antagonist, which was synthesized shortly thereafter. However, WAY-100635 turned out to be non-selective as well, having been shown to act additionally as a potent D4 receptor agonist later on.

<span class="mw-page-title-main">Tiospirone</span> Pharmaceutical drug

Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class. It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent to those of typical antipsychotics in clinical trials but without causing extrapyramidal side effects. However, development was halted and it was not marketed. Perospirone, another azapirone derivative with antipsychotic properties, was synthesized and assayed several years after tiospirone. It was found to be both more potent and more selective in comparison and was commercialized instead.

<span class="mw-page-title-main">Repinotan</span> Chemical compound

Repinotan (BAYx3702), an aminomethylchroman derivative, is a selective 5-HT1A receptor full agonist with high potency and efficacy. It has neuroprotective effects in animal studies, and was trialed in humans for reducing brain injury following head trauma. It was subsequently trialed up to phase II for treatment of stroke, but while side effects were mild and consisted mainly of nausea, repinotan failed to demonstrate sufficient efficacy to justify further clinical trials. However, repinotan continues to be investigated for other applications, and was found to be effective at counteracting the respiratory depression produced by morphine, though with slight reduction in analgesic effects.

<span class="mw-page-title-main">Sarizotan</span> Chemical compound

Sarizotan (EMD-128,130) is a selective 5-HT1A receptor agonist and D2 receptor antagonist, which has antipsychotic effects, and has also shown efficacy in reducing dyskinesias resulting from long-term anti-Parkinsonian treatment with levodopa.

Mefway (<sup>18</sup>F) Chemical compound

Mefway is a serotonin 5-HT1A receptor antagonist used in medical research, usually in the form of mefway (18F) as a positron emission tomography (PET) radiotracer.

<span class="mw-page-title-main">F-15063</span> Chemical compound

F-15,063 is an orally active potential antipsychotic, and an antagonist at the D2/D3 receptors, partial agonist at the D4 receptor, and agonist at the 5-HT1A receptors. It has greater efficacy at the 5-HT1A receptors than other antipsychotics, such as clozapine, aripiprazole, and ziprasidone. This greater efficacy may lead to enhanced antipsychotic properties, as antipsychotics that lack 5-HT1A affinity are associated with increased risk of extrapyramidal symptoms, and lack of activity against the negative symptoms of schizophrenia.

<span class="mw-page-title-main">25CN-NBOH</span> Chemical compound

25CN-NBOH is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B. A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to 5-HT2 receptors and autoradiography.

References

  1. ↑ Fornal CA, Metzler CW, Gallegos RA, Veasey SC, McCreary AC, Jacobs BL (August 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. ↑ 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. 1 2 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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  10. 1 2 Tauscher J, Verhoeff NP, Christensen BK, Hussey D, Meyer JH, Kecojevic A, et al. (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 . PMID   11282252.
  11. 1 2 Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence AD, et al. (March 2002). "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. doi:10.1006/nimg.2001.0984. PMID   11848705. S2CID   42080193.
  12. 1 2 3 4 Parsey RV, Oquendo MA, Simpson NR, Ogden RT, Van Heertum R, Arango V, Mann JJ (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. S2CID   20650203.
  13. ↑ Lundberg J, Borg J, Halldin C, Farde L (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. PMID   17874074. S2CID   22272672.
  14. 1 2 David SP, Murthy NV, Rabiner EA, Munafó MR, Johnstone EC, Jacob R, et al. (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.
  15. ↑ Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, et al. (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. S2CID   719822.
  16. ↑ Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, et al. (February 2000). "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. doi:10.1001/archpsyc.57.2.174. PMID   10665620.
  17. ↑ Nash JR, Sargent PA, Rabiner EA, Hood SD, Argyropoulos SV, Potokar JP, et al. (September 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.
  18. ↑ Lanctôt KL, Hussey DF, Herrmann N, Black SE, Rusjan PM, Wilson AA, et al. (October 2007). "A positron emission tomography study of 5-hydroxytryptamine-1A receptors in Alzheimer disease". The American Journal of Geriatric Psychiatry. 15 (10): 888–898. doi:10.1097/JGP.0b013e3180488325. PMID   17567932.
  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.
  20. ↑ Pike VW, McCarron JA, Lammertsma AA, Osman S, Hume SP, Sargent PA, et al. (April 1996). "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. doi:10.1016/0014-2999(96)00079-9. PMID   8773468.
  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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  25. ↑ 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): 704–713. PMID   10640309.
  26. ↑ Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, et al. (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): 1034–1042. doi:10.1124/jpet.104.077669. PMID   15528450. S2CID   42446435.
  27. ↑ 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): 170–178. doi:10.1038/sj.bjp.0706859. PMC   2013794 . PMID   16921393.
  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.
  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. Fox MA, Stein AR, French HT, Murphy DL (February 2010). "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. doi:10.1111/j.1476-5381.2009.00578.x. PMC   2829213 . PMID   20128812.
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