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MF-8,一种新型且有前景的基于芳基哌嗪-乙内酰脲的5-羟色胺受体拮抗剂:体外类药性质研究及体内药理学评价。

MF-8, a novel promising arylpiperazine-hydantoin based 5-HT receptor antagonist: In vitro drug-likeness studies and in vivo pharmacological evaluation.

作者信息

Latacz Gniewomir, Lubelska Annamaria, Jastrzębska-Więsek Magdalena, Partyka Anna, Kucwaj-Brysz Katarzyna, Wesołowska Anna, Kieć-Kononowicz Katarzyna, Handzlik Jadwiga

机构信息

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.

出版信息

Bioorg Med Chem Lett. 2018 Mar 1;28(5):878-883. doi: 10.1016/j.bmcl.2018.02.003. Epub 2018 Feb 3.

Abstract

We report the in vitro drug-likeness studies and in vivo pharmacological evaluation for a new potent 5-HT receptor antagonist MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylhydantoin). The in vitro tests showed good permeability, very good metabolic stability, low risk of drug-drug interactions and satisfying safety profile. Moreover, MF-8 showed excellent antidepressant-like activity in the forced swim test in rodents and promising anxiolytic-like activity in the four-plate test in mice. Regarding the potent affinity, high selectivity and antagonistic activity of MF-8 for the 5-HT receptor as well as excellent drug - like properties in vitro and confirmed in vivo pharmacological activity, MF-8 should be considered as a very significant molecule in the search for a new class of anti-depressant drugs.

摘要

我们报告了一种新型强效 5-羟色胺(5-HT)受体拮抗剂 MF-8(5-(4-氟苯基)-3-(2-羟基-3-(4-(2-甲氧基苯基)哌嗪-1-基)丙基)-5-甲基乙内酰脲)的体外类药性质研究和体内药理学评价。体外试验显示其具有良好的通透性、非常好的代谢稳定性、较低的药物相互作用风险以及令人满意的安全性。此外,MF-8 在啮齿动物的强迫游泳试验中表现出优异的抗抑郁样活性,在小鼠的四板试验中表现出有前景的抗焦虑样活性。鉴于 MF-8 对 5-HT 受体具有强效亲和力、高选择性和拮抗活性,以及体外优异的类药性质和体内得到证实的药理活性,在寻找新型抗抑郁药物的过程中,MF-8 应被视为一个非常重要的分子。

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