Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression.
Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression.
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DOI：
10.1021/jm200855b
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发表时间：
2011-10-27
影响因子：
7.3
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
--
作者：
Liu, Jianhua;Yu, Li-Fang;Eaton, J. Brek;Caldarone, Barbara;Cavino, Katie;Ruiz, Christina;Terry, Matthew;Fedolak, Allison;Wang, Daguang;Ghavami, Afshin;Lowe, David A.;Brunner, Dani;Lukas, Ronald J.;Kozikowski, Alan P.
抑郁症是一种常见的神经系统疾病，是全世界致残和自杀的主要原因之一。针对单胺转运体选择性的神经递质血清素和去甲肾上腺素的标准治疗不能帮助许多反应不良的患者。本研究促进了与α4β2-nAChR相互作用的赛替替丁- a类似物的开发，这些类似物作为部分激动剂具有良好的抗抑郁作用。结果表明，与α3β4-nAChR相比，该化合物对α4β2亚型具有高选择性，是α4β2亚型的部分激动剂，并且通过小鼠强迫游泳试验显示具有优异的抗抑郁行为特征。一种有希望的配体的初步ADMET研究显示，它具有良好的血浆蛋白结合（PPB）谱，低CYP450相关代谢，低心血管毒性，这表明它是一种有希望的先导药物，也是一种通过药物发现管道推进的候选药物。
Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with α4β2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary ADMET studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450 related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.
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影响因子：
7.3
作者：
Huang, Qingqing;Mao, Jialin;Kozikowski, Alan P.
通讯作者：
Kozikowski, Alan P.
影响因子：
10.6
作者：
Caldarone, BJ;Harrist, A;Picciotto, MR
通讯作者：
Picciotto, MR
影响因子：
3.6
作者：
Eaton, JB;Peng, JH;Lukas, RJ
通讯作者：
Lukas, RJ
影响因子：
5.8
作者：
Gotti, Cecilia;Clementi, Francesco;Zoli, Michele
通讯作者：
Zoli, Michele
影响因子：
7.3
作者：
Jamieson, Craig;Moir, Elizabeth M.;Wishart, Grant
通讯作者：
Wishart, Grant