5-Fluorowillardiine

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). 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. 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.

Applications in research

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

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.

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.

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.

References

References

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