{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:48:22Z","timestamp":1790801302323,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,3]],"date-time":"2020-01-03T00:00:00Z","timestamp":1578009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["W1232"],"award-info":[{"award-number":["W1232"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u201ccanonical\u201d 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 \u03b1+\/\u03b2\u2212 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.<\/jats:p>","DOI":"10.3390\/ijms21010334","type":"journal-article","created":{"date-parts":[[2020,1,3]],"date-time":"2020-01-03T11:55:07Z","timestamp":1578052507000},"page":"334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain\u2014Can the Promiscuity Code Be Cracked?"],"prefix":"10.3390","volume":"21","author":[{"given":"Maria Teresa","family":"Iorio","sequence":"first","affiliation":[{"name":"Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9\/163-OC, 1060 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian Daniel","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Koniuszewski","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-6034","authenticated-orcid":false,"given":"Petra","family":"Scholze","sequence":"additional","affiliation":[{"name":"Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabah","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xenia","family":"Simeone","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2946-9294","authenticated-orcid":false,"given":"Michael","family":"Schn\u00fcrch","sequence":"additional","affiliation":[{"name":"Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9\/163-OC, 1060 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5438-8368","authenticated-orcid":false,"given":"Marko D.","family":"Mihovilovic","sequence":"additional","affiliation":[{"name":"Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9\/163-OC, 1060 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9809-2649","authenticated-orcid":false,"given":"Margot","family":"Ernst","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1124\/pr.117.014449","article-title":"International Union of Basic and Clinical Pharmacology. 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