The pyrazolopyrimidine zaleplon is a hypnotic agent that acts at the benzodiazepine recognition site of GABA(A) receptors. Zaleplon, like the hypnotic agent zolpidem but unlike classical benzodiazepines, exhibits preferential affinity for type I benzodiazepine (BZ(1)/omega(1)) receptors in binding assays. The modulatory action of zaleplon at GABA(A) receptors has now been compared with those of zolpidem and the triazolobenzodiazepine triazolam. Zaleplon potentiated GABA-evoked Cl(-) currents in Xenopus oocytes expressing human GABA(A) receptor subunits with a potency that was higher at alpha1beta2gamma2 receptors than at alpha2- or alpha3-containing receptors. Zolpidem, but not triazolam, also exhibited selectivity for alpha1-containing receptors. However, the potency of zaleplon at these various receptors was one-third to one-half that of zolpidem. Zaleplon and zolpidem also differed in their actions at receptors containing the alpha5 or gamma3 subunit. Zaleplon, zolpidem, and triazolam exhibited similar patterns of efficacy among the different receptor subtypes. The affinities of zaleplon for [(3)H]flunitrazepam or t-[(35)S]butylbicyclophosphorothionate ([(35)S]TBPS) binding sites in rat brain membranes were lower than those of zolpidem or triazolam. Furthermore, zaleplon, unlike zolpidem, exhibited virtually no affinity for the peripheral type of benzodiazepine receptor.