期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 6, 页码 2422-2446出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01664
关键词
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资金
- National Institutes of Health (NIH) [R01 NS076517, R01 MH096463]
- Austrian Science Fund [I 2306-B27, W1232]
- Ministry of Education, Science and Technological Development, R. Serbia [175076]
- LING, NIMH
- Austrian Science Fund (FWF) [I2306] Funding Source: Austrian Science Fund (FWF)
Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R 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 alpha 6/beta 2/3 gamma 2 GABA(A)R 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 GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.
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