Quantitative structure-activity relationships (QSAR) between the inhibitory effect of specific t-butylbicyclophosphorothionate (TBPS) binding to rat brain P2 membrane, a lipophilic parameter, and topological indices, were studied for 33 chlorinated alicyclic insecticides such as heptachlor, aldrin and their structural analogs. This study shows that lipophilicity plays an important role in the action of cyclodiene compounds. The epoxide or ketone structural congeners, and the non-epoxide, non-ketone cyclodiene analogs exhibit two different QSARs and may bind to different regions, respectively, at the common GABA receptor. The epoxide or ketone congeners may bind at a slightly more hydrophilic region, and a negatively correlated linear relationship exists between the inhibition of TBPS-binding and lipophilicity. However, the non-epoxide, non-ketone analogs may bind at a very lipophilic region, and there is a positively correlated linear relationship between their binding and their lipophilicity. The epoxide feature of the cyclodienes seems to be an essential structural requirement for eliciting high inhibitory activity at the GABA receptor. Further the dependence of biological activity on structure can be described by a multiple-variate model with a combination of three explanatory variables among the first-, second-, third- and fourth-valence molecular connectivity indices, i.e., [superscript]1[chi][superscript] v, [superscript]2[chi][superscript] v, [superscript]3[chi][superscript] v, and [superscript]4[chi][superscript] v. High correlation coefficients (r = 0.934 to 0.941) between the biological response variable and the explanatory molecular connectivity indices demonstrated that the topological and steric attributes of the cyclodienes are structural characteristics important to for their biological activity. Electronic effects probably also contribute to the toxicity of the cyclodienes, but the parameter selected in the study, i.e., the bridge-carbon protons' chemical shift in NMR spectra, does not reveal any relationship to the TBPS binding;The information drawn from such studies will benefit our understanding of the structural determinants for the biological action of the classic cyclodiene insecticides, and future approaches could be directed at the synthesis of modified cyclodiene-type insecticides, perhaps bearing fewer chlorines in the molecular framework. A better understanding of cyclodiene QSARs will also contribute to an improved capability to assess the toxicological significance of the ubiquitous environmental residues of the cyclodienes and their degradation products.