5-Fluorowillardiine
Chemical compound
From Wikipedia, the free encyclopedia
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]
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| Other names
2-Amino-3-(5-fluoro-2,4-dioxopyrimidin-1-yl)propanoic acid | |
| Identifiers | |
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3D model (JSmol) |
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| DrugBank | |
| ECHA InfoCard | 100.162.280 |
PubChem CID |
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CompTox Dashboard (EPA) |
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| 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).
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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
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]