title: Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β- interface.
abstract: OBJECTIVE
  GABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) acts as a null modulator (antagonist) at the high affinity benzodiazepine binding site, but in addition elicits a strong enhancement of GABA-induced currents via a novel drug binding site at the extracellular α+β- interface. Here, we investigated 32 structural analogues of CGS 9895 for their ability to mediate their effects via the α1+β3- interface of GABAA receptors.
  
  
  METHODS
  GABAA receptors were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method.
  
  
  RESULTS
  We not only identified compounds with higher efficacy/potency than CGS 9895 for stimulating GABA-induced currents via the α1+β3-binding site, but also discovered compounds acting as null modulators at this site. Most of the compounds also acted as null modulators via the benzodiazepine binding site of GABAA receptors. But some of the positive allosteric modulators or null modulators exclusively exerted their action via the α+β- binding site.
  
  
  CONCLUSIONS
  Pyrazoloquinolinones and pyrazolopyridinones represent the first prototype of drug candidates mediating benzodiazepine like modulatory effects via the α+β-interface of GABAA receptors. The discovery of null modulators acting as inhibitors of the plus modulators provides a highly useful tool for the discovery of additional classes of compounds that can modulate GABAA receptors via this site, which may lead to novel therapeutic principles.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, Vienna, Austria.
authors.forename: Zdravko
authors.initials: Z
authors.lastname: Varagic
authors.forename: Laurin
authors.initials: L
authors.lastname: Wimmer
authors.forename: Michael
authors.initials: M
authors.lastname: Schnürch
authors.forename: Marko D
authors.initials: MD
authors.lastname: Mihovilovic
authors.forename: Shengming
authors.initials: S
authors.lastname: Huang
authors.forename: Sundari
authors.initials: S
authors.lastname: Rallapalli
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.forename: Pantea
authors.initials: P
authors.lastname: Mirheydari
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.forename: Werner
authors.initials: W
authors.lastname: Sieghart
authors.forename: Margot
authors.initials: M
authors.lastname: Ernst
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D005260:Female; D018757:GABA Modulators / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D018757:GABA Modulators; D011720:Pyrazoles; D011963:Receptors, GABA-A; C039232:2,5-dihydro-2-(4-methoxyphenyl)-3H-pyrazolo(4,3-c)quinolin-3-one