Structure-activity relationship of furosemide-derived compounds as antagonists of cerebellum-specific GABA(A) receptors.

The Na+-K+-2Cl- cotransporter blocker furosemide inhibits gamma-aminobutyric acid (GABA)-gated chloride currents and reverses GABA-mediated inhibition of [35S]-t-butylbicyclophosphorothionate ([35S]TBPS) binding of the cerebellar alpha6 subunit-containing GABA(A) receptors much more potently than the cerebrocortical non-alpha6 subunit-containing receptors. Of the 44 compounds studied, all precursors or derivatives of diuretics, one compound [hydrazinosulfonyl-furosemide (PF 1885)] reversed 5-microM GABA-induced inhibition of [35S]TBPS binding to cerebellar and cerebrocortical receptors. Three other compounds, all of which are structurally closely related to furosemide, were selective antago…