title: Synthesis and structure-activity relationship analysis of bicyclophosphorothionate blockers with selectivity for housefly gamma-aminobutyric acid receptor channels.
abstract: BACKGROUND
  Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of gamma-aminobutyric acid (GABA) receptor channels. Twenty-two bicyclophosphorothionates with different 3- and 4-substituents were synthesised, and [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) binding assays were performed to evaluate their affinities for housefly and rat GABA receptors.
  
  
  RESULTS
  Introduction of an isopropyl group at the 3-position enhanced the affinity of bicyclophosphorothionates for housefly GABA receptors and reduced the affinity towards rat GABA receptors. The 4-isopentyl-3-isopropylbicyclophosphorothionate showed the highest affinity for housefly GABA receptors (IC(50) = 103 nM) among the analogues tested, while the 4-cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC(50) = 125 nM). Among the bicyclophosphorothionates synthesised to date, the former analogue exhibited the highest selectivity for housefly GABA receptors, with an IC(50)(rat)/IC(50)(fly) ratio of approximately 97. Three-dimensional GABA receptor models successfully explained the structure-activity relationships of the bicyclophosphorothionates.
  
  
  CONCLUSIONS
  The results indicate that minor structural modifications of blockers can change their selectivity for insect versus mammalian GABA receptors. The substituent at the 3-position of the bicyclophosphorothionates dictates selectivity for housefly versus rat GABA receptors. This information should prove useful for the design of safer insecticides and parasiticides.
authors: School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, China.
authors: Xiu-Lian
authors: XL
authors: Ju
authors: Sayaka
authors: S
authors: Fusazaki
authors: Hiroyuki
authors: H
authors: Hishinuma
authors: Xiaomu
authors: X
authors: Qiao
authors: Izumi
authors: I
authors: Ikeda
authors: Yoshihisa
authors: Y
authors: Ozoe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D055724:Electrophysiological Phenomena / Q000187:drug effects; D018756:GABA Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006793:Houseflies / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D017905:Phosphites / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D018079:Receptors, GABA / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018756:GABA Antagonists; D017905:Phosphites; D018079:Receptors, GABA; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; C014874:2,6,7-trioxa-1-phosphabicyclo(2.2.2)octane