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. 2014 Jun 10;111(23):8607-12.
doi: 10.1073/pnas.1407379111. Epub 2014 May 27.

GABAA receptor target of tetramethylenedisulfotetramine

Chunqing Zhao  1 , Sung Hee Hwang  2 , Bruce A Buchholz  3 , Timothy S Carpenter  4 , Felice C Lightstone, Jun Yang  2 , Bruce D Hammock  5 , John E Casida  6
Affiliations

GABAA receptor target of tetramethylenedisulfotetramine

Chunqing Zhao et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A.2014 Jul 29;111(30):11223. Lightstone, Felice [corrected to Lightstone, Felice C]

Abstract

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 (GABAAR), but its molecular interaction has not been directly established for lack of a suitable radioligand to localize the binding site. We synthesized [(14)C]TETS (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)C]TETS in neuroreceptor binding studies with rat brain membranes in comparison with the standard GABAAR radioligand 4'-ethynyl-4-n-[(3)H]propylbicycloorthobenzoate ([(3)H]EBOB) (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)C]TETS and [(3)H]EBOB binding to a similar extent (r(2) = 0.71). Molecular dynamics simulations of these 14 toxicants in the pore region of the α1β2γ2 GABAAR predict unique and significant polar interactions for TETS with α1T1' and γ2S2', which are not observed for EBOB or the GABAergic insecticides. Several GABAAR modulators similarly inhibited [(14)C]TETS and [(3)H]EBOB binding, including midazolam, flurazepam, avermectin Ba1, baclofen, isoguvacine, and propofol, at 1 or 10 μM, providing an in vitro system for recognizing candidate antidotes.

Keywords: convulsant; molecular modeling; neurotoxicity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Structures of three radioligands and unlabeled insecticides or convulsants with number designations. Two numbers for TETS (1/2) and fluralaner (10/11) refer to different concentrations considered later.
Fig. 2.
Fig. 2.
Synthesis of [13C]- and [14C]TETS by serial cyclization steps in concentrated hydrochloric acid. The percentages of mono-, di-, tri-, and tetra- labeling are given in Table 1.
Fig. 3.
Fig. 3.
TETS target assayed as (A) displacement of [14C]TETS and (B) inhibition of [3H]EBOB binding in rat brain membranes.
Fig. 4.
Fig. 4.
Inhibition of [14C]TETS and [3H]EBOB binding in rat brain membranes by convulsants and insecticides at 10 µM (2 and 11) or 1 µM (all other data). Plotted from data in SI Appendix, section S3.
Fig. 5.
Fig. 5.
The equilibrated positions of TETS (1), TBPO (6), and EBOB following 40 ns of MD simulation in the pore region of the α1β2γ2 GABAAR model, with views from the side (Left, the front two M2 helices have been removed for clarity), and views from the bottom of the pore (Right). The red dashed lines signify the common binding region around the 2′ “contact zone.” The contact zone is the region where a compound can make contacts to 2′, either from above or below the residue. The view down the pore shows that at the 1′2′ region, TETS makes primarily polar interactions to the α and γ subunits (hydrogen bonds shown as dashed magenta lines), TBPO makes both polar and hydrophobic interactions, and EBOB makes nonspecific hydrophobic interactions with this 1′2′ ring of residues.
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