Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 169, Issue 2, Pages 371-383Publisher
WILEY-BLACKWELL
DOI: 10.1111/bph.12151
Keywords
GABAA receptors; CGS 9895; pyrazoloquinolinones; pyrazolopyridinones; + binding site; positive modulators; null modulators; benzodiazepine binding site
Categories
Funding
- Austrian Science Fund [P19653-B11]
- FP7 project [HEALTH-F4-2008-202088]
- Austrian Ministry of Science and Research
- National Institutes of Health [MH-046851]
- Austrian Science Fund FWF [W1232]
- Austrian Science Fund (FWF) [P19653] Funding Source: Austrian Science Fund (FWF)
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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 + interface. Here, we investigated 32 structural analogues of CGS 9895 for their ability to mediate their effects via the 1+3 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 1+3-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 + binding site. Conclusion and Implications Pyrazoloquinolinones and pyrazolopyridinones represent the first prototype of drug candidates mediating benzodiazepine like modulatory effects via the +-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. Linked Article This article is accompanied by Varagic etal., pp. 384399 of this issue. To view this article visit http://dx.doi.org/10.1111/bph.12153
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