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J Med Chem. 2018 Mar 22;61(6):2422-2446. doi: 10.1021/acs.jmedchem.7b01664. Epub 2018 Mar 6.

Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABAAR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability.

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Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery , University of Wisconsin-Milwaukee , 3210 N. Cramer St. , Milwaukee , Wisconsin 53211 , United States.
Department of Pharmacology, Faculty of Pharmacy , University of Belgrade , Vojvode Stepe 450 , 11221 Belgrade , Serbia.
Department of Molecular Neurosciences, Center for Brain Research , Medical University of Vienna , Spitalgasse 4 , A-1090 Vienna , Austria.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy , University of Belgrade , Vojvode Stepe 450 , 11221 Belgrade , Serbia.
TU Wien-Institute of Applied Synthetic Chemistry , Getreidemarkt 9/163 , A-1060 Vienna , Austria.
Graduate Institute of Acupuncture Science , China Medical University , Taichung 40402 , Taiwan.


Recent reports indicate that α6β2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6β2/3γ2 subtypes.

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