Abstract
About forty bicyclic phosphates (BPs) and phosphorothionates (analogs of 2, 6, 7-trioxa-1-phosphabicyclo[2.2.2]octane) were synthesized to elucidate the mode of action of the cage convulsants. Some of them were highly toxic to the mouse and the housefly, although the former was more sensitive than the latter. The Hansch-Fujita analysis suggested that hydrophobic, steric and electronic interactions between the bridgehead substituent and putative binding site (s) in vivo played an important role in BP poisoning. Phosphorus compounds of this class were unique in that their anticholinesterase activity was extremely low despite their high reactivity under alkaline conditions. The bicyclic phosphates suppressed the miniature inhibitory junction potentials recorded from the longitudinal muscle of the earthworm. A specific binding site for toxic BPs was identified in the rat brain and was shown to be related to the γ-aminobutyric acid (GABA) receptor-ionophore complex by a ligand-receptor binding assay using 4-n-propyl[2, 3-3H]BP as a ligand. Interactions between BPs and the site of action were speculated by using cyclodextrin as a specific BP binding site model. Taken together, these findings indicate that the bridged bicyclic phosphorus esters antagonize the action of the neurotransmitter GABA by binding to a site linked to chloride ion channels in the postsynaptic membrane.
