(S)-(-)-5-Fluorowillardiine

(S)-(-)-5-Fluorowillardiine is a potent and specific AMPAR agonist.

References:
[1]. Hawkinson JE, et al. Effects of thiocyanate and AMPA receptor ligands on (S)-5-fluorowillardiine, (S)-AMPA and (R,S)-AMPA binding. Eur J Pharmacol. 1997 Jun 25;329(2-3):213-21. [2]. Kessler M, et al. Use of [3H]fluorowillardiine to study properties of AMPA receptor allosteric modulators. Brain Res. 2006 Mar 3;1076(1):25-41. [3]. Rembach A, et al. Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS. J Neurosci Res. 2004 Aug 15;77(4):573-82.

Selective loss of binding sites for the glutamate receptor ligands [3H]kainate and (S)-[3H]5-fluorowillardiine in the brains of rats with acute liver failure.[Pubmed:9049210]

Hepatology. 1997 Mar;25(3):631-5.

There is increasing evidence that alterations of glutamatergic function are implicated in the pathogenesis of central nervous system consequences of acute liver failure. The aim of the study was to assess the integrity of glutamate receptors in the brain in experimental ischemic liver failure using quantitative receptor autoradiography and the selective ligands [3H]MK801 (for N-methyl-D-aspartate [NMDA] sites), [3H]5-fluorowillardiine (for non-NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] subclass sites), and [3H]kainate (for non-NMDA, kainate subclass sites). At coma stages of encephalopathy, a selective loss of up to 60% of binding sites for the kainate- and AMPA-receptor ligands was observed in cerebral cortical and hippocampal structures as well as in the hypothalamus and cerebellum. The finding of a selective loss of AMPA sites at coma stages of encephalopathy in this model of acute liver failure is consistent with previous electrophysiological reports of inhibition of AMPA-mediated neuronal depolarization resulting from exposure of hippocampal neurons to millimolar concentrations of ammonia. On the other hand, the present study showed that binding sites for the NMDA-receptor ligand [3H]MK801 at coma stages of encephalopathy in acute liver failure were within normal limits in all brain structures examined. NMDA sites are uniquely neuronal, whereas kainate and AMPA sites are localized on both neurons and astrocytes. Therefore, the selective loss of non-NMDA sites in acute liver failure may also reflect astrocytic changes in this condition. Because astrocytic glutamate receptors are implicated in K+ and neurotransmitter reuptake, alterations in their density could result in altered neuronal excitability and thus be responsible for the neurological dysfunction characteristic of hepatic encephalopathy in acute liver failure.

Characterization of the pharmacology and regional distribution of (S)-[3H]-5-fluorowillardiine binding in rat brain.[Pubmed:8640342]

Br J Pharmacol. 1995 Oct;116(3):2033-9.

1. This study examined the binding of the new radioligand (S)-[3H]-5-fluorowillardiine to rat brain synaptic membranes. Specific binding represented greater than 80% of the total binding and was increased by 10% in the presence of 100mM potassium thiocyanate (KSCN). 2. In the absence of KSCN, (S)-[3H]-5-fluorowillardiine identified two binding sites with KD1=22.5 nM, Bmax1=1.4 pmol mg(-1) protein and KD2=1.5 microM, Bmax2=10.8 pmol mg(-1) protein. In the presence of 100 mM KSCN the affinities of both the binding sites were increased, yielding values of KD1=6.9 nM and KD2=0.4 microM KSCN was without effect on the Bmax values. 3. (S)-[3H]-5-fluorowillardiine binding was displaced by non-NMDA receptor ligands with the rank order of potency: 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX) > domoate > (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionice acid (AMPA) = L-glutamate > 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) > kainate >> (R)-5-fluorowellardiine. In contrast, both N-methyl-D-aspartate (NMDA) and the metabotropic glutamate receptor agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were inactive. 4. By use of quantitative autoradiography the regional distribution of (S)-[3H]-5-fluorowillardiine binding in rat brain was assessed. The highest levels of binding were in the dentate gyrus and the CA1 region of the hippocampus. Lower levels of binding were detected in the cerebral cortex, olfactory system, lateral septum, caudate putamen and nucleus accumbens. 5. We conclude that the pharmacological profile and regional distribution of (S)-[3H]-5-fluorowillardiine binding is consistent with its specific interaction with AMPA receptors.

(S)-5-fluorowillardiine-mediated neurotoxicity in cultured murine cortical neurones occurs via AMPA and kainate receptors.[Pubmed:8957243]

Eur J Pharmacol. 1996 Oct 24;314(1-2):249-54.

We have examined the neurotoxic effects of kainate, (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and the novel AMPA-receptor preferring agonist (S)-5-fluorowillardiine in murine cultured cortical neurones. Kainate induced > 90% cell death (EC50 65 microM) and (S)-AMPA only about 50% cell death (EC50 3.1 microM), both in a monophasic dose-dependent manner. (S)-5-Fluorowillardiine also killed > 90% of neurones, however, in a biphasic dose-dependent manner (EC50 0.70 and 170 microM). Additionally, the neurotoxic effects of (S)-AMPA and (S)-5-fluorowillardiine (high-affinity component) were attenuated by the AMPA receptor antagonists LY293558 ((3,S,4aR, 6R,8aR)-6[2h91 H-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinol ine- 3-carboxylic acid). A component of kainate and (S)-5-fluorowillardiine (low-affinity component) neurotoxicity was blocked by the low-affinity kainate receptor antagonist NS-102 (5-nitro-6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime). We have shown that both kainate and (S)-AMPA can effect substantial cell death in cortical neurones and that the novel agonist (S)-5-fluorowillardiine exerts its excitotoxicity through both AMPA- and kainate-preferring receptors.

Effects of thiocyanate and AMPA receptor ligands on (S)-5-fluorowillardiine, (S)-AMPA and (R,S)-AMPA binding.[Pubmed:9226415]

Eur J Pharmacol. 1997 Jun 25;329(2-3):213-21.

AMPA receptors can be labeled using the agonist radioligands [3H](R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H](R,S)-AMPA), [3H](S)-AMPA or [3H](S)-5-fluorowillardiine. In the presence of KSCN, [3H](R,S)-AMPA and [3H](S)-AMPA bind to a single population of sites in rat brain membranes, whereas [3H](S)-5-fluorowillardiine binds with two affinity components. KSCN increased the affinity of the low affinity [3H](S)-5-fluorowillardiine component > 4-fold and increased the density of both components 1.5-1.7-fold, arguing against KSCN-induced interconversion of low to high affinity states. KSCN, which promotes receptor desensitization, increased the potency of AMPA isomers, (S)-5-fluorowillardiine, quisqualate and cyclothiazide for inhibition of [3H](S)-5-fluorowillardiine binding suggesting that these ligands discriminate desensitized and nondesensitized receptors. In contrast, KSCN did not greatly affect the potency of glutamate, kainate, or competitive antagonists suggesting that these ligands do not discriminate desensitized and nondesensitized receptors. In the presence of KSCN, the rank order potency for agonists and antagonists was similar or identical in all assays indicating that the three radioligands bind identical glutamate recognition sites, a conclusion supported by their identical total receptor density. However, AMPA isomers displayed 6-10-fold higher potency for displacement of [3H](S)- or (R,S)-AMPA relative to [3H](S)-5-fluorowillardiine binding. This finding, coupled with the marked two component binding by [3H](S)-5-fluorowillardiine but not [3H](S)- or (R,S)-AMPA, suggests qualitative differences between the interaction of these ligands with the agonist recognition site.