Design, Synthesis, and Pharmacological Evaluation of Novel beta 2/3 Subunit-Selective gamma-Aminobutyric Acid Type A (GABA(A)) Receptor Modulators
| Autor: | Christoph Schwarzer, Ernst Urban, Vittorio Pace, Steffen Hering, Thierry Langer, Stefan Boehm, Serena Monticelli, Thomas Seidel, Sophia Khom, Isabella Salzer, Marco Stadler, Wolfgang Holzer, Denise Luger |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Chemistry GABAA receptor Voltage clamp Loreclezole Pharmacology Valerenic acid 01 natural sciences Aminobutyric acid 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound In vivo Drug Discovery medicine Molecular Medicine Potency Receptor 030304 developmental biology medicine.drug |
| Popis: | Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABAAR) is considered to exert fewer side effects compared to unselective clinically used drugs. Here, the β2/3 subunit-selective GABAAR modulators valerenic acid (VA) and loreclezole (LOR) guided the synthesis of novel subunit-selective ligands with simplified structures. We studied their effects on GABAARs expressed in Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Five compounds showed significantly more efficacious modulation of GABA-evoked currents than VA and LOR with retained potency and selectivity. Compound 18 [(E)-2–Cyano-3-(2,4-dichlorophenyl)but-2-enamide] induced the highest maximal modulation of GABA-induced chloride currents (Emax: 3114 ± 242%), while 12 [(Z)-3-(2,4-dichlorophenyl)but-2-enenitrile] displayed the highest potency (EC50: 13 ± 2 μM). Furthermore, in hippocampal neurons 12 facilitated phasic and tonic GABAergic inhibition, and in vivo studies revealed significantly more potent protect... |
| Databáze: | OpenAIRE |
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