Recognition of tetramethylenedisulfotetramine and related sulfamides by the brain GABA-gated chloride channel and a cyclodiene-sensitive monoclonal antibody.
Aldrin and many other cyclodiene and polychlorocycloalkane insecticides interact with both the [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding site of the mammalian brain gamma-aminobutyric acid (GABA) gated chloride channel and several cyclodiene monoclonal antibodies (MAbs) at concentrations ranging from 0.06 to 8.7 microM. A survey of other classes of GABAA receptor antagonists (including picrotoxinin and several trioxabicyclooctanes) for possible interactions with the cyclodiene MAbs revealed only one potent inhibitor, the heteroadamantane tetramethylenedisulfotetramine (TETS) [mouse intraperitoneal LD50 0.24 mg/kg; TBPS binding site IC50 0.5 microM as a competitive inhibitor (Scatchard analysis); cyclodiene MAb IC50 3 microM]. These findings prompted comparative studies on the structure-activity relationships of other sulfamides as they apply to both the ligand-nerve and ligand-MAb interactions. TETS is active on only one (MAb 8H11) of four cyclodiene MAbs. Several hetero(homo)adamantanes were synthesized and compared with TETS for neurotoxicity and recognition by the TETS-sensitive cyclodiene MAb. The toxicity to mice and/or houseflies decreases in the following order: TETS much greater than the heterotetracyclic compound hexamethylenetrisulfohexamine (HEXS) and two TETS analogues in which one sulfamide group is replaced with o-phenylenediamine or 1,1-dimethyl-1,2-diaminoethane much greater than seven other hetero(homo)adamantanes. The TETS-sensitive cyclodiene MAb recognizes HEXS (IC50 0.4 microM) and, to a lesser extent, two related sulfamides. However, the cross-reactivity noted for the cyclodiene insecticides and TETS relative to the GABA-gated chloride channel (inhibition of TBPS binding) and the cyclodiene MAb does not extend to several TETS analogues including HEXS.(ABSTRACT TRUNCATED AT 250 WORDS)
Esser
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Department of Entomological Sciences, and Hybridoma Facility, College of Natural Resources, University of California, Berkeley 94720.
Karu
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AE
Toia
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RF
Casida
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JE
D000577:Amides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001667:Binding, Competitive; D001952:Bridged-Ring Compounds / Q000378:metabolism* / Q000494:pharmacology; D018118:Chloride Channels; D003516:Cycloparaffins / Q000276:immunology* / Q000494:pharmacology; D018756:GABA Antagonists; D006793:Houseflies; D007124:Immunoenzyme Techniques; D007306:Insecticides / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009417:Nerve Tissue / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000577:Amides; D000911:Antibodies, Monoclonal; D001952:Bridged-Ring Compounds; D018118:Chloride Channels; D003516:Cycloparaffins; D018756:GABA Antagonists; D007306:Insecticides; D008565:Membrane Proteins; D005680:gamma-Aminobutyric Acid; C010349:tetramethylenedisulfotetramine