Polycyclic dinitriles: a novel class of potent GABAergic insecticides provides a new radioligand, [3H]BIDN

Invert Neurosci. 1997 Sep-Dec;3(2-3):261-8. doi: 10.1007/BF02480383.

Abstract

The polycyclic dinitriles are a potent class of insecticides which are non-competitive GABA (gamma-aminobutyric acid) antagonists acting at the convulsant site. Comparison with other classes of GABA convulsant site ligands using molecular modelling has shown significant structural similarities. We have developed a pharmacophore model which unifies this class and some previous classes of GABA convulsants. Key pharmacophore elements are a polarizable functionality separated by a fixed distance from two H-bond accepting elements. This model is based on information from X-ray crystal structures and Sybyl using the Tripos force field. Using this pharmacophore model, numerous structural modifications were explored to enhance understanding of structure-activity relationships at the GABA receptor convulsant site of insects and mammals. A radiolabelled bicyclic dinitrile, [3H]BIDN [3H]3,3-bis-trifluoromethyl-bicyclo[2,2,1]heptane-2,2-dicarbonitrile+ ++), was prepared from this area of chemistry and was used as a probe for the interaction of polycyclic dinitriles at the target site.

MeSH terms

  • Animals
  • Binding, Competitive
  • Bridged Bicyclo Compounds / chemistry*
  • Bridged Bicyclo Compounds / metabolism*
  • Cell Membrane / metabolism
  • Coleoptera
  • GABA Antagonists / chemistry*
  • GABA Antagonists / metabolism*
  • Insecticides / chemistry*
  • Models, Molecular
  • Nitriles / chemistry*
  • Nitriles / metabolism*
  • Picrotoxin / analogs & derivatives
  • Picrotoxin / chemistry
  • Picrotoxin / metabolism
  • Radioligand Assay*
  • Receptors, GABA / analysis*
  • Receptors, GABA / metabolism
  • Sesterterpenes
  • Tritium

Substances

  • Bridged Bicyclo Compounds
  • GABA Antagonists
  • Insecticides
  • Nitriles
  • Receptors, GABA
  • Sesterterpenes
  • Tritium
  • Picrotoxin
  • 3,3-bis(trifluoromethyl)bicyclo(2.2.1)heptane-2,2-dicarbonitrile
  • picrotoxinin