Polycyclic dinitriles: a novel class of potent GABAergic insecticides provides a new radioligand, [3H]BIDN.
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.
Rauh
J J
JJ
DuPont Agricultural Products, Newark, DE 19714-0030, USA. James.J.Rauh@usa.dupont.com
Holyoke
C W
CW
Kleier
D A
DA
Presnail
J K
JK
Benner
E A
EA
Cordova
D
D
Howard
M H
MH
Hosie
A M
AM
Buckingham
S D
SD
Baylis
H A
HA
Sattelle
D B
DB
D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D001517:Coleoptera; D018756:GABA Antagonists / Q000737:chemistry* / Q000378:metabolism*; D007306:Insecticides / Q000737:chemistry*; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry* / Q000378:metabolism*; D010852:Picrotoxin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D018079:Receptors, GABA / Q000032:analysis* / Q000378:metabolism; D054830:Sesterterpenes; D014316:Tritium; D005466:Fluorocarbons
D001643:Bridged Bicyclo Compounds; D018756:GABA Antagonists; D007306:Insecticides; D009570:Nitriles; D010852:Picrotoxin; D018079:Receptors, GABA; D054830:Sesterterpenes; D014316:Tritium; C098123:3,3-bis(trifluoromethyl)bicyclo(2.2.1)heptane-2,2-dicarbonitrile; D005466:Fluorocarbons; C022961:picrotoxinin