METABOLISM OF THE INSECTICIDALLY ACTIVE GABA-A RECEPTOR ANTAGONIST 4-SEC-BUTYL-1-(4-CYANOPHENYL)-2,6,7-TRIOXABICYCLO[2.2.2]OCTANE

4-sec-[3,4-3H2]Butyl-l-(4-cyanophenyl)-2,6,7-trioxabicyclo[2.2.2]octane (referred to as [3H]COB) was examined as an example of a new class of insecticidally active compounds that block the γ-aminobutyric acid gated chloride channel. Metabolites were identified by thin-layer cochromatography with standards from synthesis and by consideration of their hydrolytic and oxidative degradation products formed in situ on two-dimensional silica gel chromatoplates. Metabolism of [3H]COB by mouse liver and housefly abdomen microsomes is dependent on fortification with NADPH. The O-methylene and sec-butyl sites are sensitive to oxidation. Each carbon of the sec-butyl group is individually functionalized with strong preference for the methylene site in the mouse but not the housefly microsomal system. O-Methylene hydroxylation initiates spontaneous cage opening to form an aldehyde that undergoes metabolic reduction, ultimately yielding the same cyanobenzoate ester of 2,2-bis- (hydroxymethyl)-3-methylpentan-l-ol formed by direct hydrolysis. Houseflies injected with [3H]COB form many if not all of the same metabolites, with major products being the aforementioned cyanoben-zoate, the orthoester oxidized at the sec-butyl methylene site, and polar conjugates. © 1990, American Chemical Society. All rights reserved.