{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:44:24Z","timestamp":1790192664157,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (USA)","award":["DA-043204"],"award-info":[{"award-number":["DA-043204"]}]},{"name":"National Institutes of Health (USA)","award":["DA054177"],"award-info":[{"award-number":["DA054177"]}]},{"name":"National Institutes of Health (USA)","award":["AA029023"],"award-info":[{"award-number":["AA029023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>GABA mediates inhibitory actions through various GABAA receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of \u03b12\/3 GABAARs can treat mood and anxiety, while \u03b15 GABAA-Rs can treat anxiety, depression, and cognitive performance. GL-II-73 and MP-III-022, \u03b15-positive allosteric modulators have shown promising results in animal models of chronic stress, aging, and cognitive disorders, including MDD, schizophrenia, autism, and Alzheimer\u2019s disease. Described in this article is how small changes in the structure of imidazodiazepine substituents can greatly impact the subtype selectivity of benzodiazepine GABAAR. To investigate alternate and potentially more effective therapeutic compounds, modifications were made to the structure of imidazodiazepine 1 to synthesize different amide analogs. The novel ligands were screened at the NIMH PDSP against a panel of 47 receptors, ion channels, including hERG, and transporters to identify on- and off-target interactions. Any ligands with significant inhibition in primary binding were subjected to secondary binding assays to determine their Ki values. The newly synthesized imidazodiazepines were found to have variable affinities for the benzodiazepine site and negligible or no binding to any off-target profile receptors that could cause other physiological problems.<\/jats:p>","DOI":"10.3390\/molecules28124771","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T02:03:19Z","timestamp":1686794599000},"page":"4771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synthesis and Receptor Binding Studies of \u03b15 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders"],"prefix":"10.3390","volume":"28","author":[{"given":"Dishary","family":"Sharmin","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin Milwaukee, Milwaukee, WI 53201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Yeunus","family":"Mian","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin Milwaukee, Milwaukee, WI 53201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Marcotte","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-603X","authenticated-orcid":false,"given":"Thomas D.","family":"Prevot","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Sibille","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada"},{"name":"Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5T 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Witkin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin Milwaukee, Milwaukee, WI 53201, USA"},{"name":"Laboratory of Antiepileptic Drug Discovery, Ascension, St. Vincent, Indianapolis, IN 46260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-3022","authenticated-orcid":false,"given":"James M.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin Milwaukee, Milwaukee, WI 53201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1001\/jamapsychiatry.2013.3059","article-title":"Diversity of neuronal inhibition: A path to novel treatments for neuropsychiatric disorders","volume":"71","author":"Benham","year":"2014","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5829","DOI":"10.1021\/jm040863t","article-title":"An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties","volume":"47","author":"Chambers","year":"2004","journal-title":"J. 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