γ-BHC: Its history and mystery--why is only γ-BHC insecticidal?

Among BHC isomers (benzene hexachloride, C6H6Cl6, theoretically eight ones), seven isomers (α,β,γ,δ,ε,η,ι) including one racemate (α) were isolated and their configurations were elucidated. Among the seven isomers, only γ-BHC has a potent insecticidal activity. γ-BHC poisoning symptoms accompanied by the violent tremor of the body, particularly in the legs and abnormal fluttering were consistently correlated with central nervous system effects, and the action was shown on the ganglia rather than on the isolated nerve cord. The excitatory effects of γ-BHC poisoning on spontaneous activity and synaptic function in the sixth abdominal ganglion of the American cockroach result from the presynaptic action that causes an excessive release of acetylcholine. F. Matsumura found the phenomena of cross resistance between γ-BHC, cyclodiene insecticides and GABA (γ-aminobutyric acid) antagonist, picrotoxinin, and concluded that the primary target of γ-BHC is the picrotoxinin receptor in the GABA receptor Cl- ion channel complex (GABA-gated chloride channel) and its antagonistic action on GABA receptor results in an excessive release of Ach. In order to study the structure-activity relationship, a number of γ-BHC analogs, in which one or two chlorine atoms on dl or meso position(s) of the γ-BHC molecule were replaced by various substituents such as hydrogen, halogens other than chlorine and alkoxy groups, etc. were synthesized. In the case of dl type-analogs, there is an optimum volume for dl-substituents, which corresponds to Cl. The question why γ-BHC is insecticidal and other BHC isomers are not remains unsolved.