GABA_A receptor target of tetramethylenedisulfotetramine

Chunqing Zhao; Sung Hee Hwang; Bruce A. BuchholzTimothy S. CarpenterFelice C. LightstoneJun YangBruce D. HammockJohn E. Casida

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GABA_A receptor target of tetramethylenedisulfotetramine

机译：GABA_A receptor target of tetramethylenedisulfotetramine

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Use of the highly toxic and easily prepared rodenticide tetramethylenedisulfotetramine (TETS) was banned after thousands of accidental or intentional human poisonings, but it is of continued concern as a chemical threat agent. TETS is a noncompetitive blocker of the GABA type A receptor (GABA_AR), but its molecular interaction has not been directly established for lack of a suitable radioligand to localize the binding site. We synthesized ~(14)CTETS (14 mCi/mmol, radiochemical purity >99) by reacting sulfamide with H~(14)CHO and s-trioxane then completion of the sequential cyclization with excess HCHO. The outstanding radiocarbon sensitivity of accelerator mass spectrometry (AMS) allowed the use of ~(14)CTETS in neuroreceptor binding studies with rat brain membranes in comparison with the standard GABA_AR radioligand 4′-ethynyl-4-n-~3Hpropylbicycloorthobenzoate (~3HEBOB) (46 Ci/mmol), illustrating the use of AMS for characterizing the binding sites of high-affinity ~(14)C radioligands. Fourteen noncompetitive antagonists of widely diverse chemotypes assayed at 1 or 10 μM inhibited ~(14)CTETS and ~3HEBOB binding to a similar extent (r~2 = 0.71). Molecular dynamics simulations of these 14 toxicants in the pore region of the α1β2γ2 GABA_AR predict unique and significant polar interactions for TETS with α1T1′ and γ_2S2′, which are not observed for EBOB or the GABAergic insecticides. Several GABA_AR modulators similarly inhibited ~(14)CTETS and ~3HEBOB binding, including midazolam, flurazepam, avermectin Ba1, baclofen, isoguvacine, and propofol, at 1 or 10 μM, providing an in vitro system for recognizing candidate antidotes.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第23期|8607-8612|共6页
作者
Chunqing Zhao; Sung Hee Hwang; Bruce A. BuchholzTimothy S. CarpenterFelice C. LightstoneJun YangBruce D. HammockJohn E. Casida;
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作者单位

Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California, Berkeley, CA 94720;

Department of Entomology, College of Agricultural and Environmental Science, University of California, Davis, CA 95616;

Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94551Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94551;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
neurotoxicity; convulsant; molecular modeling;

GABA_A receptor target of tetramethylenedisulfotetramine

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