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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers
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Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers

机译：氟化吲哚-咪唑缀合物：选择性口服生物可利用的5-HT7受体低碱性激动剂，潜在的神经性止痛药

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摘要

The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, K-i (5-HT7R) = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain C-max = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：由于其涉及多种生理功能和疾病，5-HT7受体最近受到了很多关注。可用的分子探针的不足促使氟化3-（1-烷基-1H-咪唑-5-基）-1H-吲哚设计为新一代选择性5-HT7受体激动剂。一种有效的和药物状激动剂，3-（1-乙基-1H-咪唑-5-基）-5-碘-4-氟-1H-吲哚（AGH-192,35，Ki（5-HT7R）= 4通过用SER5.42优化作为假定的伴侣，通过优化卤素键形成来鉴定NM。该化合物的特征在于优异的水溶解度，对相关CNS靶标的高选择性，高代谢稳定性，口服生物利用度和低细胞毒性。在I.P之后发现，在I.P中发现脑中的血液，中半衰期和高峰浓度的快速吸收。 （2.5mg / kg）小鼠施用。因此，AGH-192可以作为长寻求的工具化合物在研究5-HT7受体功能以及潜在的镇痛药中，该镇痛作用是在神经性疼痛的小鼠模型中观察到的抗血巧效果。 （c）2019年Elsevier Masson SAS。版权所有。

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