Photoactivatable 2-[(4'-azido)tetrafluorophenyl]-5-tert-butyl-1,3-dithiane bissulfone and related compounds as candidate irreversible probes for the GABA-gated chloride channels

Syntheses of 2-substituted photoactivatable derivatives of 5-tert-butyl-1,3-dithiane and their oxidized bis-sulfone derivatives are described with the aim of developing original photoaffinity probes for the GABA-gated chloride channel. Diazocyclohexadienone as well as fluorinated arylazido derivatives were chosen as photosensitive moieties. The dithiane molecules were synthesized by condensation of 2-tert-butylpropane-1,3-dithiol with the appropriate substituted benzaldehydes. The diazocyclohexadienonyl derivatives were synthesized either by diazotization of the corresponding dithiane arylamine precursors (compounds 1, 2, 17, and 18) or by diazotization of the bis-sulfone dithiane arylamine (compounds 19 and 20). The reversible binding properties of the photosensitive probes were established on bovine cortex P2 membranes by displacement of [3H]-tert-butylbicycloorthobenzoate. While the bromo-substituted diazocyclohexadienoyl dithiane derivatives (compounds 1 and 2) exhibited a Ki of about 2-4 microM 2-(4'-azidotetrafluorophenyl)-5-tert-butyl-1,3-dithiane-bis-sulfon e (compound 3) gave a Ki of 0.2 microM. On irradiation, probe 3 produced a 25% irreversible loss of TBOB binding sites in brain membranes. Moreover, this loss was fully protectable by TBOB, demonstrating the specificity of the photochemical inactivation by compound 3 for the convulsant site of the GABAA receptor.