Role of Alkyl Groups at the Three Position of Bicyclophosphorothionates in Interaction with Insect GABA-Gated Chloride Channel

Abstract

Eight 3-alkyl-4-propyl-2, 6, 7-trioxa-1-phosphabicyclo [2. 2. 2] octane 1-sulfides were synthesized and assayed by three systems to characterize the topography of t-butylbicyclophos-phorothionate (TBPS)-binding sites in the insect GABA-gated chloride channel. In topical application to piperonyl butoxide (PB)-pretreated houseflies, the rank order of 3-substituents giving high insecticidal activity was i-Pr>Me=H>Et=t-Bu>s-Bu>n-Pr. In injection to PB-pretreated German cockroaches, the order was t-Bu=i-Pr>Me=Et>n-Pr=s-Bu=H. In both assays, the n-Bu and i-Bu analogs were almost inactive. In [³⁵S]TBPS-binding assays on housefly head membranes, the substitution with t-Bu, i-Pr and s-Bu groups gave the most potent analogs with IC₅₀ values of ≤ 1μM, followed by the Me, Et and n-Pr analogs, the unsubstituted compound and the n-Bu analog. The i-Bu analog was less potent than these compounds. The results indicate that the introduction of a 3-alkyl group with the length of one to three carbon atoms results in an increase in the affinity for TBPS-binding sites (only the branching at the 2 position of the alkyl group exerts the opposite effect) and that the t-Bu and i-Pr groups are optimal substituents.