Modulation of the picrotoxin receptor by fluorinated ethyl, methyl-butyrolactones

A number of investigators have shown that γ-butyrolactones bind to the picrotoxin site on the γ-aminobutyric acid (GABA) receptor. We examined the effects of three fluorinated γ-butyrolactone derivatives on GABA currents and synaptic currents in cultured hippocampal neurons. α-(2,2,2-trifluoroethyl)-α-methyl-γ-butyrolactone was a partial picrotoxin agonist, meaning that like picrotoxin, it blocked GABA currents, but not completely. This action is in marked contrast to that of its parent compound, α-ethyl-α-methyl-γ-butyrolactone, which is a mixed inverse agonist/antagonist, enhancing GABA currents at low GABA concentration (≤ 1 μM) and antagonizing picrotoxin block of GABA currents at higher GABA concentrations (~30 μM). The properties of two difluorinated derivatives were found to be very different from the trifluorinated compound. Both α-(1,1-difluoroethyl)-α-methyl-γ-butyrolactone and α-(1,1-difluoroethyl)-α-methyl-γ-thiobutyrolactone dramatically increased the current produced by low concentrations of GABA. The former had less marked inverse agonist effects at higher GABA concentration but behaved instead like a picrotoxin antagonist. In addition, α-(1,1-difluoroethyl)-α-methyl-γ-butyrolactone reduced both excitatory and inhibitory synaptic current suggesting a separate effect on presynaptic transmitter release through an unknown mechanism. These experiments support the hypothesis that β-butyrolactones can have a variety of effects at the picrotoxin receptors and indicate that specific properties of these compounds can be altered drastically by fluorination.