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Volume 21
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10.3390/ijms21010334
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Article

GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain—Can the Promiscuity Code Be Cracked?

by
Maria Teresa Iorio
1,
Florian Daniel Vogel
2,
Filip Koniuszewski
2,
Petra Scholze
3,
Sabah Rehman
2,
Xenia Simeone
2,
Michael Schnürch
1,
Marko D. Mihovilovic
1 and
Margot Ernst
2,*
1
Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
2
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria
3
Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(1), 334; https://doi.org/10.3390/ijms21010334
Submission received: 29 November 2019 / Revised: 20 December 2019 / Accepted: 26 December 2019 / Published: 3 January 2020
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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Abstract

Many allosteric binding sites that modulate gamma aminobutyric acid (GABA) effects have been described in heteropentameric GABA type A (GABAA) receptors, among them sites for benzodiazepines, pyrazoloquinolinones and etomidate. Diazepam not only binds at the high affinity extracellular “canonical” site, but also at sites in the transmembrane domain. Many ligands of the benzodiazepine binding site interact also with homologous sites in the extracellular domain, among them the pyrazoloquinolinones that exert modulation at extracellular α+/β− sites. Additional interaction of this chemotype with the sites for etomidate has also been described. We have recently described a new indole-based scaffold with pharmacophore features highly similar to pyrazoloquinolinones as a novel class of GABAA receptor modulators. Contrary to what the pharmacophore overlap suggests, the ligand presented here behaves very differently from the identically substituted pyrazoloquinolinone. Structural evidence demonstrates that small changes in pharmacophore features can induce radical changes in ligand binding properties. Analysis of published data reveals that many chemotypes display a strong tendency to interact promiscuously with binding sites in the transmembrane domain and others in the extracellular domain of the same receptor. Further structural investigations of this phenomenon should enable a more targeted path to less promiscuous ligands, potentially reducing side effect liabilities.
Keywords: receptors; GABAA; benzodiazepines (BZ); binding sites; etomidate receptors; GABAA; benzodiazepines (BZ); binding sites; etomidate
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MDPI and ACS Style

Iorio, M.T.; Vogel, F.D.; Koniuszewski, F.; Scholze, P.; Rehman, S.; Simeone, X.; Schnürch, M.; Mihovilovic, M.D.; Ernst, M. GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain—Can the Promiscuity Code Be Cracked? Int. J. Mol. Sci. 2020, 21, 334. https://doi.org/10.3390/ijms21010334

AMA Style

Iorio MT, Vogel FD, Koniuszewski F, Scholze P, Rehman S, Simeone X, Schnürch M, Mihovilovic MD, Ernst M. GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain—Can the Promiscuity Code Be Cracked? International Journal of Molecular Sciences. 2020; 21(1):334. https://doi.org/10.3390/ijms21010334

Chicago/Turabian Style

Iorio, Maria Teresa, Florian Daniel Vogel, Filip Koniuszewski, Petra Scholze, Sabah Rehman, Xenia Simeone, Michael Schnürch, Marko D. Mihovilovic, and Margot Ernst. 2020. "GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain—Can the Promiscuity Code Be Cracked?" International Journal of Molecular Sciences 21, no. 1: 334. https://doi.org/10.3390/ijms21010334

APA Style

Iorio, M. T., Vogel, F. D., Koniuszewski, F., Scholze, P., Rehman, S., Simeone, X., Schnürch, M., Mihovilovic, M. D., & Ernst, M. (2020). GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain—Can the Promiscuity Code Be Cracked? International Journal of Molecular Sciences, 21(1), 334. https://doi.org/10.3390/ijms21010334

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