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Br J Pharmacol
2013 May 01;1692:371-83. doi: 10.1111/bph.12151.
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Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β- interface.
Varagic Z
,
Wimmer L
,
Schnürch M
,
Mihovilovic MD
,
Huang S
,
Rallapalli S
,
Cook JM
,
Mirheydari P
,
Ecker GF
,
Sieghart W
,
Ernst M
.
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BACKGROUND AND PURPOSE: 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.
EXPERIMENTAL APPROACH: GABAA receptors were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method.
KEY 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.
CONCLUSION AND IMPLICATIONS: 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.
Baumann,
Subunit arrangement of gamma-aminobutyric acid type A receptors.
2001, Pubmed,
Xenbase
Baumann,
Subunit arrangement of gamma-aminobutyric acid type A receptors.
2001,
Pubmed
,
Xenbase
Baur,
Covalent modification of GABAA receptor isoforms by a diazepam analogue provides evidence for a novel benzodiazepine binding site that prevents modulation by these drugs.
2008,
Pubmed
,
Xenbase
Brown,
In vivo determination of efficacy of pyrazoloquinolinones at the benzodiazepine receptor.
1984,
Pubmed
Ebert,
Extensive heterogeneity of recombinant gamma-aminobutyric acidA receptors expressed in alpha 4 beta 3 gamma 2-transfected human embryonic kidney 293 cells.
1996,
Pubmed
Ernst,
Comparative modeling of GABA(A) receptors: limits, insights, future developments.
2003,
Pubmed
Ernst,
Comparative models of GABAA receptor extracellular and transmembrane domains: important insights in pharmacology and function.
2005,
Pubmed
Farrar,
Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer.
1999,
Pubmed
Fryer,
Structure-activity relationship studies at the benzodiazepine receptor (BZR): a comparison of the substitutent effects of pyrazoloquinolinone analogs.
1993,
Pubmed
He,
Studies of molecular pharmacophore/receptor models for GABAA/BzR subtypes: binding affinities of symmetrically substituted pyrazolo[4,3-c]quinolin-3-ones at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.
1999,
Pubmed
Horton,
Gene splicing by overlap extension.
1993,
Pubmed
Khom,
Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands - in vitro and in vivo characterization.
2010,
Pubmed
,
Xenbase
Li,
Synthesis, in vitro affinity, and efficacy of a bis 8-ethynyl-4H-imidazo[1,5a]- [1,4]benzodiazepine analogue, the first bivalent alpha5 subtype selective BzR/GABA(A) antagonist.
2003,
Pubmed
,
Xenbase
Loo,
Benzodiazepine receptor modulation of [35S]TBPS binding to the chloride channel. Noncompetitive inhibition of classical benzodiazepines and competitive inhibition of the partial agonist, CGS 9895, by CGS 8216.
1987,
Pubmed
Mortensen,
Extrasynaptic alphabeta subunit GABAA receptors on rat hippocampal pyramidal neurons.
2006,
Pubmed
Ogris,
Affinity of various benzodiazepine site ligands in mice with a point mutation in the GABA(A) receptor gamma2 subunit.
2004,
Pubmed
Olsen,
International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update.
2008,
Pubmed
Ramerstorfer,
The GABAA receptor alpha+beta- interface: a novel target for subtype selective drugs.
2011,
Pubmed
,
Xenbase
Ramerstorfer,
The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.
2010,
Pubmed
Richter,
Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands.
2012,
Pubmed
Sieghart,
A novel GABA(A) receptor pharmacology: drugs interacting with the α(+) β(-) interface.
2012,
Pubmed
Sieghart,
Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes.
1995,
Pubmed
Sigel,
Mapping of the benzodiazepine recognition site on GABA(A) receptors.
2002,
Pubmed
Sigel,
The effect of subunit composition of rat brain GABAA receptors on channel function.
1990,
Pubmed
,
Xenbase
Smith,
Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux.
2001,
Pubmed
Smith,
Functional domains of GABAA receptors.
1995,
Pubmed
Thomet,
A novel positive allosteric modulator of the GABA(A) receptor: the action of (+)-ROD188.
2000,
Pubmed
,
Xenbase
Tretter,
Stoichiometry and assembly of a recombinant GABAA receptor subtype.
1997,
Pubmed
Varagic,
Subtype selectivity of α+β- site ligands of GABAA receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors.
2013,
Pubmed
,
Xenbase
Williams,
CGS 20625, a novel pyrazolopyridine anxiolytic.
1989,
Pubmed
