5-Fluorowillardiine is a selectiveagonist for theAMPA receptor,[1][2][3] with only limited effects at thekainate receptor.[4] It is anexcitotoxicneurotoxin when usedin vivo and so is rarely used in intact animals, but it is widely used to selectively stimulate AMPA receptorsin 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 inMariosousa willardiana andAcacia sensu lato.[8][9]
The name is unusual as it has two successivei's. This is not atypo.
(S)-5-Fluorowillardiine activity has been studiedin vitro in a variety of neural tissues. In mouse embryo hippocampal neurons, it was found to desensitize AMPA/kainate receptors with anEC50 of 1.5 μM – 7 times more potent than racemicAMPA (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] Whilein 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]
Radiolabeled 5-fluorowillardiine has been used to study the distribution ofionotropic glutamate receptors in rodent brains.[13] It has also been used to evaluate the effects of variousallosteric modulators of the AMPA receptor.[14]
5-Fluorowillardiine is derived from the nitrogenous baseuracil found inRNA. It is one member of a family of willardiine compounds, which share uracil or a substituted uracil as anamino acid side chain. 5-Fluorowillardiine exists as two distinctisomers:
(2R) orD
(2S) orL
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]
^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.ISBN978-0-07-176651-7.
^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.PMID8957243.
^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.PMID16112106.
^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.PMID9357531.
^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.PMID9357531.
^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.
