Interaction of Lindane Isomers with Chloride Currents in Insect Membranes: Steric Requirements for Channel Modulation and Block.

Electrophysiological methods were used to characterize the modulatory effects of hexachlorocyclohexane isomers on GABA-activated chloride currents in dissociated locust neurones. Conductance changes associated with hyperpolarising responses (or outward voltage-clamped currents), evoked by brief GABA pulses, were inhibited by the gamma-isomer at 0.01-1 μM. The antagonistic action was noncompetitive and voltage-independent: the concentration required for half-maximal block was <0.01 μM. The rate of equilibration with the membrane/receptor was inversely proportional to the concentration applied and was not dependent upon agonist-induced channel gating: effects were only partially reversible with extensive washing. In contrast the noninsecticidal beta-isomer was a low-affinity (>/=10 μM) positive modulator of the inhibitory chloride channels. The modulatory action was voltage-dependent (more pronounced for inward currents at hyperpolarised potentials), did not reflect changes in chloride equilibrium potential, and was completely reversible. Nicotinic acetylcholine receptors were consistently antagonised by the beta-isomer at 10 μM. The above results were interpreted by computer-assisted modelling and are discussed in the context of a pharmacophore model for picrotoxinin and convulsant insecticides. The gamma-isomer overlays well with picrotoxinin and a convulsant butyrolactone whereas the beta-isomer and anticonvulsant butyrolactones conform to a different template. Liganding mechanisms and comparative/species differences in chloride channel pharmacology are discussed in the context of potential for development of invertebrate-selective pesticides.