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A fluorinated derivative of an anticonvulsant γ-butyrolactone [α-(1,1-difluoroethyl)-α-methyl-γ-butyrolactone; γ-DFGBL] was synthesized as a probe for NMR spectroscopic observation of the drug in brain tissue. The fluorinated compound is an efficacious anticonvulsant in mice, and inhibits the specific binding of [35S]t-butylbicyclophosphorothionate ([35SITBPS) to mouse brain membranes with a concentration dependence similar to that of the non-fluorinated compound α-ethyl-α-methyl-γ-butyrolactone. Quantitative 19F-NMR spectroscopic studies, coupled with Chromatographic measurements of drug tissue concentration, showed that virtually all of the α-DFGBL in brain was NMR-observable and that, following intraperitoneal injection, α-DFGBL rapidly achieved millimolar concentrations in brain. The 19F-NMR spectra of a α-DFGBL in brain and liver tissue were broad (1-2 ppm) and complex, exhibiting multiple chemical shift features. The major chemical shift features in these spectra were assigned on the basis of differential extraction and comparison of 19F spin-spin relaxation times (T2s) and 19F chemical shifts of α-DFGBL in tissue to those in pure solvents. The major feature at 10.4 ppm in the tissue spectra was assigned to a weakly polar, membrane-associated environment for the fluorinated compound, while the feature at 11.2 ppm was assigned to an aqueous environment for α-DFGBL. The drug was in slow exchange between these two environments in brain. In addition, the feature at lowest field (9.7-9.8 ppm) was identified as a water-soluble hydroxy-acid metabolite of α-DFGBL produced by the liver. These data indicate that γ-butyrolactone anticonvulsants achieve high concentrations in brain, where they exist in several, largely membrane-associated, environments. These findings are consistent with the purported action of the γ-butyrolactones as low-affinity modulators of γ-aminobutyric acid-A channels.

Original languageEnglish
Pages (from-to)949-959
Number of pages11
JournalBiochemical Pharmacology
Issue number4
StatePublished - Feb 24 1993


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