1-(4-Ethynylphenyl)-4-substituted-2,6,7-trioxabicyclo[2.2.2]octanes: effect of 4-substituent on toxicity to houseflies and mice and potency at the GABA-gated chloride channel

1-(4-Ethynylphenyl)-2,6,7-trioxabicyclo[2.2.2]octanes with appropriate 4-substituents are among the most potent insecticides and GABA(A) receptor antagonists. Thirty-five analogues were prepared with varying 4-substituents comprising six n-alkyl, seven cycloalkyl, six branched alkyl, five alkenyl, eight aryl, and three others. About half of these compounds are highly potent insecticides with topical LD50S for adult houseflies of 0.1-1 microgram/g and with 2- to 50-fold synergism by piperonyl butoxide. Most of the same compounds are also very active in mammalian systems with mouse intraperitoneal LD50S of 0.1-1 mg/kg and IC50S of 0.4-5 nM for inhibiting the GABA-gated chloride channel (tert-butylbicyclophosphorothionate or TBPS assay). Potency in the TBPS receptor assay generally correlates with the toxicity to mice (r = 0.76; n = 30). Particularly effective 4-substituents in these assays are C3-4 n-alkyl, C3-6 cycloalkyl, tert-butyl (near optimal) and several other C3-5 branched alkyls, and phenyl or fluorophenyl. Some selective toxicity to mice is conferred by dimethylamino and to houseflies by n-butyl and 4-fluorophenyl substituents, indicating possible differences in receptor specificity