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Towards functional selectivity for α6ß3γ2 GABAA receptors: a series of novel pyrazoloquinolinones.
Treven, Marco; Siebert, David C B; Holzinger, Raphael; Bampali, Konstantina; Fabjan, Jure; Varagic, Zdravko; Wimmer, Laurin; Steudle, Friederike; Scholze, Petra; Schnürch, Michael; Mihovilovic, Marko D; Ernst, Margot.
Affiliation
  • Treven M; Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • Siebert DCB; Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria.
  • Holzinger R; Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • Bampali K; Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • Fabjan J; Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • Varagic Z; Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • Wimmer L; Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria.
  • Steudle F; Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • Scholze P; Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University Vienna, Vienna, Austria.
  • Schnürch M; Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria.
  • Mihovilovic MD; Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria.
  • Ernst M; Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, Vienna, Austria.
Br J Pharmacol ; 175(3): 419-428, 2018 02.
Article in En | MEDLINE | ID: mdl-29127702
ABSTRACT
BACKGROUND AND

PURPOSE:

The GABAA receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/ß- interfaces, using a systematically varied series of pyrazoloquinolinones. EXPERIMENTAL

APPROACH:

Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA-elicited currents by the newly synthesized and reference compounds were investigated by the two-electrode voltage clamp method. KEY

RESULTS:

We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at α6ß3γ2 GABAA receptors with nearly no residual activity at the other αxß3γ2 (x = 1-5) subtypes. This modulation was independent of affinity for α+/γ- interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular α+/ß- interfaces. CONCLUSION AND IMPLICATIONS These results constitute a major step towards a potential selective positive modulation of certain α6-containing GABAA receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABAA receptor isoforms.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrazoles / Receptors, GABA-A / Quinolones / GABA Modulators Limits: Animals Language: En Journal: Br J Pharmacol Year: 2018 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrazoles / Receptors, GABA-A / Quinolones / GABA Modulators Limits: Animals Language: En Journal: Br J Pharmacol Year: 2018 Document type: Article Affiliation country: