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Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABA(A)) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both α2β(2/3)γ2 (α2BzR) and α3BzR (and/or α2/α3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100mg/kg and was devoid of sedative properties. Copyright © 2012 Elsevier Ltd. All rights reserved.


Ojas A Namjoshi, Zhi-jian Wang, Sundari K Rallapalli, Edward Merle Johnson, Yun-Teng Johnson, Hanna Ng, Joachim Ramerstorfer, Zdravko Varagic, Werner Sieghart, Samarpan Majumder, Bryan L Roth, James K Rowlett, James M Cook. Search for α3β₂/₃γ2 subtype selective ligands that are stable on human liver microsomes. Bioorganic & medicinal chemistry. 2013 Jan 1;21(1):93-101

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PMID: 23218469

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