5-Fluorowillardiine
Skeletal formula of (2S)-5-fluorowillardiine
Names
Other names
2-Amino-3-(5-fluoro-2,4-dioxopyrimidin-1-yl)propanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.162.280
UNII
  • InChI=1S/C7H8FN3O4/c8-3-1-11(2-4(9)6(13)14)7(15)10-5(3)12/h1,4H,2,9H2,(H,13,14)(H,10,12,15) checkY
    Key: DBWPFHJYSTVBCZ-UHFFFAOYSA-N checkY
  • InChI=1/C7H8FN3O4/c8-3-1-11(2-4(9)6(13)14)7(15)10-5(3)12/h1,4H,2,9H2,(H,13,14)(H,10,12,15)
    Key: DBWPFHJYSTVBCZ-UHFFFAOYAR
  • NC(CN1C=C(F)C(=O)N=C1O)C(O)=O
Properties
C7H8FN3O4
Molar mass 217.156 g·mol−1
log P -1.168
Acidity (pKa) 2.118
Basicity (pKb) 11.879
Isoelectric point 4.28
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

5-Fluorowillardiine is a selective agonist for the AMPA receptor,[1][2][3] with only limited effects at the kainate receptor.[4] It is an excitotoxic neurotoxin when used in vivo and so is rarely used in intact animals, but it is widely used to selectively stimulate AMPA receptors in vitro.[5][6][7] It is structurally similar to the compound willardiine, which is also an agonist for the AMPA and kainate receptors. Willardiine occurs naturally in Mariosousa willardiana and Acacia sensu lato.[8][9]

The name is unusual as it has two successive i's. This is not a typo.

Toxicity

(S)-5-Fluorowillardiine activity has been studied in vitro in a variety of neural tissues. In mouse embryo hippocampal neurons, it was found to desensitize AMPA/kainate receptors with an EC50 of 1.5 μM –— 7 times more potent than racemic AMPA (EC50 of 11 μM).[10] In another study, (S)-5-Fluorowillardiine showed biphasic dose-dependent neurotoxicity in cultural rodent cortical neurons, with EC50 values of 0.70 and 170 μM.[11] While in vivo research is sparse, a study in 5-day-old mice injected with the closely related AMPA/kainate agonist (S)-5-Bromowillardiine showed cortical and white matter damage. AMPA antagonists reduced the extent of the damage in a dose-dependent fashion.[12]

Applications in research

Radiolabeled 5-fluorowillardiine has been used to study the distribution of ionotropic glutamate receptors in rodent brains.[13] It has also been used to evaluate the effects of various allosteric modulators of the AMPA receptor.[14]

Chemistry

Structure and activity

Synthesis of 5-fluorowillardiine

5-fluorowillardiine is derived from the nitrogenous base uracil found in RNA. It is one member of a family of willardiine compounds, which share uracil or a substituted uracil as an amino acid side chain. 5-Fluorowillardiine exists as two distinct isomers:

  • (2R) or D
  • (2S) or L

The particularly high affinity of 5-fluorowillardiine for the AMPA receptor is attributed to its fluorine substituent at the 5-position of the ring, which is electron-withdrawing and small enough to not interfere with binding. By contrast, related willardiine derivatives with larger nonpolar electron withdrawing groups exhibit greater affinity for kainate receptors than 5-fluorowillardiine, and less affinity for AMPA receptors.[15]

The binding of 5-fluorowillardiine to the AMPA receptor is driven by entropy when its ring is uncharged. When the ring is deprotonated and has a negative charge, a favorable change in enthalpy primarily drives binding. Because the pKa values of halogenated willardiine derivates are approximately 8 (7.98 for 5-Fluorowillardiine), binding is mostly driven by an increase in entropy at physiological pH.[16]

Synthesis

The synthesis of 5-Fluorowillardiine may be achieved by using 5-Fluorouracil as a nucleophile to open a specialized lactone in an SN2 reaction. Another straightforward approach is to perform a Strecker amino acid synthesis.[17][18]

References

  1. ↑ Patneau, DK; Mayer, ML; Jane, DE; Watkins, JC (1992). "Activation and Desensitization of AMPA / Kainate Receptors by Novel Derivatives of Willardiine". Journal of Neuroscience. 12 (2): 595–606. doi:10.1523/JNEUROSCI.12-02-00595.1992. PMC 6575614. PMID 1371315.
  2. ↑ Hawkins, LM; Beaver, KM; Jane, DE; Taylor, PM; Sunter, DC; Roberts, PJ (1995). "Characterization of the pharmacology and regional distribution of (S)-3H-5-fluorowillardiine binding in rat brain". British Journal of Pharmacology. 116 (3): 2033–9. doi:10.1111/j.1476-5381.1995.tb16408.x. PMC 1908955. PMID 8640342.
  3. ↑ Lunn, ML; Ganakas, AM; Mercer, LD; Lawrence, AJ; Beart, PM (1996). "Localisation and properties of AMPA-insensitive kainate sites: receptor autoradiography and gene expression in rat brain". Neuroscience Letters. 204 (1–2): 121–4. doi:10.1016/0304-3940(96)12335-1. PMID 8929993. S2CID 36885666.
  4. ↑ Larm, JA; Cheung, NS; Beart, PM (1996). "(S)-5-fluorowillardiine-mediated neurotoxicity in cultured murine cortical neurones occurs via AMPA and kainate receptors". European Journal of Pharmacology. 314 (1–2): 249–54. doi:10.1016/S0014-2999(96)00633-4. PMID 8957243.
  5. ↑ Jensen, RJ (1999). "Responses of directionally selective retinal ganglion cells to activation of AMPA glutamate receptors". Visual Neuroscience. 16 (2): 205–19. doi:10.1017/s0952523899162023. PMID 10367956. S2CID 42955027.
  6. ↑ Olivera, S; Rodriguez-Ithurralde, D; Henley, JM (2001). "Regional localization and developmental profile of acetylcholinesterase-evoked increases in 3H-5-fluorowillardiine binding to AMPA receptors in rat brain". British Journal of Pharmacology. 133 (7): 1055–62. doi:10.1038/sj.bjp.0704167. PMC 1572873. PMID 11487516.
  7. ↑ Kessler, M; Arai, AC (2006). "Use of 3H fluorowillardiine to study properties of AMPA receptor allosteric modulators". Brain Research. 1076 (1): 25–41. doi:10.1016/j.brainres.2005.09.024. PMID 16256076. S2CID 28267484.
  8. ↑ Klaassen, C. D.; John Barr Watkins (2010). "Toxic Agents" (PDF). Casarett and Doull's essentials of toxicology. USA: McGraw-Hill Prof Med/Tech. p. 374. ISBN 978-0-07-176651-7.
  9. ↑ Atta-ur- Rahman (2000). "Interference of Alkaloids" (PDF). Bioactive Natural Products (Part B), Part 2. Amsterdam: Alsevier Science B. V. p. 72. ISBN 9780080542010.
  10. ↑ Patneau, DK; Mayer, ML; Jane, DE; Watkins, JC (1 February 1992). "Activation and desensitization of AMPA/kainate receptors by novel derivatives of willardiine". The Journal of Neuroscience. 12 (2): 595–606. doi:10.1523/JNEUROSCI.12-02-00595.1992. PMC 6575614. PMID 1371315.
  11. ↑ Larm, Jari A.; Cheung, Nam Sang; Beart, Philip M. (October 1996). "(S)-5-Fluorowillardiine-mediated neurotoxicity in cultured murine cortical neurones occurs via AMPA and kainate receptors". European Journal of Pharmacology. 314 (1–2): 249–254. doi:10.1016/S0014-2999(96)00633-4. PMID 8957243.
  12. ↑ Gressens, Pierre; Spedding, Michael; Gigler, Gabor; Kertesz, Szabolcs; Villa, Pascal; Medja, Fadia; Williamson, Toni; Kapus, Gabor; Levay, Gyorgy; Szenasi, Gabor; Barkoczy, Jozsef; Harsing, Laszlo G. (September 2005). "The effects of AMPA receptor antagonists in models of stroke and neurodegeneration". European Journal of Pharmacology. 519 (1–2): 58–67. doi:10.1016/j.ejphar.2005.06.031. PMID 16112106.
  13. ↑ Hawkins, L.M.; Beaver, K.M.; Jane, D.E.; Taylor, P.M.; Sunter, D.C.; Roberts, P.J. (October 1995). "Characterization of the pharmacology and regional distribution of (S)-[3H]-5-fluorowillardiine binding in rat brain". British Journal of Pharmacology. 116 (3): 2033–2039. doi:10.1111/j.1476-5381.1995.tb16408.x. PMC 1908955. PMID 8640342.
  14. ↑ Kessler, Markus; Arai, Amy C. (March 2006). "Use of [3H]fluorowillardiine to study properties of AMPA receptor allosteric modulators". Brain Research. 1076 (1): 25–41. doi:10.1016/j.brainres.2005.09.024. PMID 16256076. S2CID 28267484.
  15. ↑ Jane, David E.; Hoo, Ken; Kamboj, Raj; Deverill, Michele; Bleakman, David; Mandelzys, Allan (October 1997). "Synthesis of Willardiine and 6-Azawillardiine Analogs: Pharmacological Characterization on Cloned Homomeric Human AMPA and Kainate Receptor Subtypes". Journal of Medicinal Chemistry. 40 (22): 3645–3650. doi:10.1021/jm9702387. PMID 9357531.
  16. ↑ Martinez, Madeline; Ahmed, Ahmed H.; Loh, Adrienne P.; Oswald, Robert E. (5 June 2014). "Thermodynamics and Mechanism of the Interaction of Willardiine Partial Agonists with a Glutamate Receptor: Implications for Drug Development". Biochemistry. 53 (23): 3790–3795. doi:10.1021/bi500511m. PMC 4215890. PMID 24850223.
  17. ↑ Jane, David E.; Hoo, Ken; Kamboj, Raj; Deverill, Michele; Bleakman, David; Mandelzys, Allan (October 1997). "Synthesis of Willardiine and 6-Azawillardiine Analogs: Pharmacological Characterization on Cloned Homomeric Human AMPA and Kainate Receptor Subtypes". Journal of Medicinal Chemistry. 40 (22): 3645–3650. doi:10.1021/jm9702387. PMID 9357531.
  18. ↑ Dewar, J. H.; Shaw, G. (1962). "110. Purines, pyrimidines, and imidazoles. Part XVII. A synthesis of willardiine". Journal of the Chemical Society (Resumed): 583. doi:10.1039/JR9620000583.
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