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

Chem Res Toxicol. Mar-Apr 1991;4(2):162-7. doi: 10.1021/tx00020a007.

Abstract

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)

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amides / metabolism*
  • Amides / pharmacology
  • Animals
  • Antibodies, Monoclonal / metabolism*
  • Binding, Competitive
  • Bridged-Ring Compounds / metabolism*
  • Bridged-Ring Compounds / pharmacology
  • Chloride Channels
  • Cycloparaffins / immunology*
  • Cycloparaffins / pharmacology
  • GABA Antagonists*
  • Houseflies
  • Immunoenzyme Techniques
  • Insecticides / pharmacology
  • Ion Channel Gating / drug effects*
  • Kinetics
  • Male
  • Membrane Proteins / drug effects
  • Membrane Proteins / metabolism*
  • Mice
  • Nerve Tissue / drug effects
  • Nerve Tissue / physiology
  • Structure-Activity Relationship
  • gamma-Aminobutyric Acid / physiology

Substances

  • Amides
  • Antibodies, Monoclonal
  • Bridged-Ring Compounds
  • Chloride Channels
  • Cycloparaffins
  • GABA Antagonists
  • Insecticides
  • Membrane Proteins
  • gamma-Aminobutyric Acid
  • tetramethylenedisulfotetramine