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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 antagonists for the cerebellar receptors comparable to the lead compound. Still, the diuretic and GABAergic structure-activity relationships differ, since we found potent diuretic structures lacking GABA antagonistic activity. Further development of the GABAergic potency of furosemide derivatives can now focus on the modification of the carboxyl group, replaceable by tetrazole but not by sulfonic or phosphinic acids and the furanyl moiety which could be substituted by thienyl and benzyl groups.