Recognition of tetramethylenedisulfotetramine and related sulfamides by the brain GABA-gated chloride channel and a cyclodiene-sensitive monoclonal antibody

• Published in: Chemical research in toxicology Vol. 4; no. 2; pp. 162 - 167
• Main Authors: Esser, Thomas, Karu, Alexander E, Toia, Robert F, Casida, John E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-1991
• Subjects: Amides - metabolism; Amides - pharmacology; Animals; Antibodies, Monoclonal - metabolism; Binding, Competitive; Biological and medical sciences; Bridged-Ring Compounds - metabolism; Bridged-Ring Compounds - pharmacology; Chloride Channels; Cycloparaffins - immunology; Cycloparaffins - pharmacology; GABA Antagonists; gamma-Aminobutyric Acid - physiology; Houseflies; Immunoenzyme Techniques; Insecticides - pharmacology; Ion Channel Gating - drug effects; Kinetics; Male; Medical sciences; Membrane Proteins - drug effects; Membrane Proteins - metabolism; Mice; Nerve Tissue - drug effects; Nerve Tissue - physiology; Pesticides, fertilizers and other agrochemicals toxicology; Structure-Activity Relationship; Toxicology; Gabaergic receptor; Nervous system diseases; Insecticide; Structure activity relation; Toxicity; Chlorides; Ionic channel; Binding site; Antagonist; Monoclonal antibody
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx00020a007

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.