5-Fluorowillardiine

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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 Edit this at Wikidata
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 ?)

5-Fluorowillardiine is a selective

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

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

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. PMID 1371315
    .
  2. PMID 8640342
    .
  3. S2CID 36885666
    .
  4. PMID 8957243
    .
  5. S2CID 42955027
    .
  6. PMID 11487516
    .
  7. S2CID 28267484
    .
  8. ISBN 978-0-07-176651-7
    .
  9. ISBN 9780080542010
    .
  10. PMID 1371315
    .
  11. PMID 8957243
    .
  12. PMID 16112106
    .
  13. PMID 8640342
    .
  14. S2CID 28267484
    .
  15. PMID 9357531
    .
  16. PMID 24850223
    .
  17. PMID 9357531
    .
  18. doi:10.1039/JR9620000583
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=5-Fluorowillardiine&oldid=1175943181"