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A number of widely diverse compounds that show inhibitory activities at the picrotoxinin binding sites in housefly and rat GABA receptors were investigated by using the distance comparison technique (DISCOtech) and comparative molecular field analysis (CoMFA) methods to explore the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds. These compounds consist of three diverse types of noncompetitive GABA receptor antagonists, i.e., trioxabicyclooctanes and their derivatives, picrodendrins and related terpenoids, and fipronil and its analogs. For investigation of the structural requirements for inhibitory activity at the picrotoxinin binding site of GABA receptor, DISCOtech pharmacophore models containing one center of hydrophobic ring and two hydrogen bond acceptor atoms for both housefly-head and rat-brain GABA receptors were constructed, respectively. In particular, the interacting areas in housefly receptors appear to be wider than that in rat receptors, the differences between rat and housefly receptor models implicate the selectivity of noncompetitive GABA receptor antagonists. In addition, corresponding CoMFA models with good statistical indices (r(2)>0.9 and q(2)>0.5) were also obtained. These models can be used as guidance for the development of new compounds with high activities and selectivities.