SITES OF ACTION OF NONCOMPETITIVE GABA ANTAGONISTS IN HOUSEFLIES AND RATS - 3-DIMENSIONAL QSAR ANALYSIS

Quantitative structure-activity relationships for insecticidal activit y (against houseflies) and competitive activity against a specific [S- 35]tert-butyl-bicyclophosphorothionate binding (to rat brain membranes ) of some picrotoxinin-type 4-aminobutyric acid antagonists, including gamma-BHC, endosulfan, bicyclophosphates, dioxatricyclododecenes and related compounds, were examined three-dimensionally using comparative molecular field analysis (CoMFA). The antagonists were classified int o two series according to their molecular shapes: i.e. whether their s tructure was 'linearly' extended beyond the 'mast-head' position of th e 'boat-like' skeletons (series 1) or not (series 2). The CoMFA showed that the slopes in steric and electrostatic fields around the molecul e were significant for both series in governing the potency variations in insecticidal and binding activities. Hydrophobicity, a possible fa ctor controlling transport behaviour of compounds, was significant in governing variations in insecticidal activity, but not for the case of the rat membrane binding. Assuming that there is a slight topological difference between series 1 and 2 compounds in terms of the mode of b inding with the housefly receptor site, the insecticidal activity was analysable with a single equation for the combined set of compounds, b ut the rat membrane binding was not. The sterically and electrostatica lly favourable regions surrounding the molecular series indicated by C oMFA were roughly located at positions so as to interact with the bind ing subsites on the receptors proposed previously.