SPIROSULTAM-LY219048 - A NEW CHEMICAL CLASS OF INSECTICIDE ACTING UPON THE GABA RECEPTOR CHLORIDE IONOPHORE COMPLEX

This study assessed the toxicity and mode of action of a new experimen tal insecticide, LY219048 in insects and mammals. LY219048 produced ra pid convulsions in mice and had LD50 values of 0.7 mg kg-1 and 4 mg kg -1 after intracerebral and intraperitoneal injection, respectively. In initial screens against insects, LY219048 showed low activity against the German cockroach (Blatella germanica L.). Lethality from dietary exposure required one to two weeks, even at concentrations as high as 10000 mg kg-1 (LC50 = 485 mg kg-1). In contrast, it had an LC50 value of 8.3 mg kg-1 against insecticide-susceptible Drosophila melanogaster (Meig.) when synergized with piperonyl butoxide. Significant resistan ce to LY219048 (> 12-fold) was detected in a cyclodiene-resistant stra in of D. melanogaster possessing an altered target site resistance mec hanism. This finding suggested that LY219048 blocked the 4-aminobutyri c acid (GABA)-gated chloride channel in a manner similar to that of th e cyclodienes. In physiological studies in larval D. melanogaster cent ral neurons, LY219048 antagonized the reduction of firing caused by 1 mM GABA. Dose-response experiments showed that the ED50 for blocking i nhibition under these conditions was c. 1 muM. Studies of Cl-36 uptake into bovine brain synaptosomes found that LY219048 was a potent antag onist. At 10 muM it completely blocked chloride flux stimulated by 50 muM GABA. LY219048 competitively displaced [H-3]TBOB binding from bovi ne brain membranes, with an IC50 of 42 nM, which was comparable to val ues determined for TBPS (35 nM) and picrotoxinin (267 nM). There was l ittle or no displacement (< 25%) of [H-3]flunitrazepam or [H-3]muscimo l binding by 10 muM LY219048. Taken together, these results provide st rong evidence that this new chemical class of insecticide manifests it s acute toxicity by blocking the GABA-gated chloride channel.