3D-QSAR Studies On GABA_A Receptor Noncompetitive Antagonists

γ-Aminobutyric acid (GABA) receptor is the target of someinsecticides, such as polychlorocycloalkanes (PCCAs), fipronil andavermectins (AVMs), and it also mediates many neuro-diseases, includingHuntington's disease, epilepsy, alcoholism, schizophrenia, insomnia,Parkinson's disease and mental retardation et al. So GABA receptor,especially GABA_A receptor, is a hot spot for development of drugs inrelated fields. In this paper, the compounds binding in GABA_A receptorwere considered in order to design new compounds with high activity andlow toxicity.Based on a lot of published experimental data of these four types ofGABA_A receptor noncompetitive antagonists bind in housefly and ratGABA receptors, 3D-quantitative structure-activity relationship (3D-QSAR)studies on these four dissimilar types of compounds were performed usingcomparative molecular field analysis (CoMFA) in this thesis.Main contents are as follows:1. CoMFA studies were performed on a set ofpolychlorocycloalkanes (PCCAs) classified as series 1 and series 2 whichbind in rat GABA receptor, and some structural information of the derivedmodel was obtained and disscussed. The subsites (B and C) whichcompounds in series 1 bind in are slightly different with those ofcompounds in series 2.2. CoMFA studies were performed on four sets oftrioxabicyclooctanes (TBOs) which bind in housefly and rat GABAreceptor respectively, and the similarities and differences of four modelswere discussed which would be helpful to design new compounds withhigher selectivity.3. CoMFA and CoMSIA studies were performed on two sets ofpicrodendrin homologues (PDDs) which bind in housefly and rat GABAreceptor respectively, and the similarities and differences of four models(including two CoMFA models and two CoMSIA models) weredisscussed. Some conclusions were obtained, such as R₁ substitute is very important to the selectivity of compounds bining in housefly and ratGABA receptors.4. CoMFA studies were performed on a set of fipronil homologueswhich bind in housefly GABA receptor, and the results based on differentalignments were dissucussed. The model based on rigid field fit wasananlysised and it was obtained that the bulk and electric property ofsubstitutes at -CN, NH₂ and -CF₃ strongly influence the bio-activity ofcompounds.5. DISCOtech and CoMFA studies were performed on all types ofcompounds which bind in housefly and rat GABA receptor respectively,and some common characters and differences of the pharmacophoremodels were obtained. Two pharmacophore models including two H-bondacceptor centers and one hydrophobic center were obtained. Finally, it ispresumed that the binding pocket of rat receptor is slightly smaller thanthat of housefly receptor.Good pharmacophore models and CoMFA models were achieved inthis thesis. Especially, the common characters obtained from these fourtypes of compounds are not reported in published paper, and it is firstlyanalysised in related fields.