Synthesis And Biological Activity Of GABA Receptor Antagonist Bicyclophosphorothionates

γ-Aminobutyric acid(GABA) is an important inhibitory transmitter in central nervous system(CNS),whose inhibition is mediated by GABA receptor A type(GABA_AR),and plays an important role in neural(inhibitory) excitability.GABA receptor is the target of some sorts of insecticides,such as organochlorine,fipronil and avermectin.Besides,it is closely related to human neurologic diseases.Results of study indicate that caged bicyclophosphates can be used as fungicides,acaricides,herbicides etc.Scientists focus their attention on this type of compound because of its high symmetric caged structure,biological activity,as well as its particular mechanism.Electrophysiological and radio-ligand binding studies show that bicyclophosphorothionate is a noncompetitive antagonist acting on picrotoxinin site of GABA_A receptor,and it appears high insecticidal activities to houseflies.The aim of this work is to discover novel lead compound for development of insecticide that are safe, specific and highly effective.In this study,two synthetic routes were designed and fourteen 3-cyano-4-alkyl caged bicyclophosphate compounds were synthesized,while, six 3-aryl bicyclophosphorothionates and eight 4-substituted compounds were synthesized via another two routes.Two types of intermediates were synthesized as well.Twenty of twenty-eight compounds were characterized by EI-MS,¹H NMR spectra and elemental analysis.In addition,potency of twenty compounds in inhibition of[³H]EBOB binding to rat and housefly GABA receptor were investigated,the results show that these compounds have relatively high receptor binding activity and certain selectivity between rat and housefly GABA receptors at 10^-5 mol/L.