Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II.
Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II.
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DOI：
10.1021/jm400510u
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发表时间：
2013-07-11
影响因子：
7.3
通讯作者：
Kozikowski AP
中科院分区：
文献类型：
--
作者：
Zhang HK;Yu LF;Eaton JB;Whiteaker P;Onajole OK;Hanania T;Brunner D;Lukas RJ;Kozikowski AP
最近，在我们的努力中发现了带有含环丙烷侧链的3-吡啶基醚支架，以创造新型抗抑郁药，作为α4β2-烟碱乙酰胆碱受体的部分激动剂。在这项研究中，一个系统的结构-活性关系进行了调查的氮杂环丁烷部分存在于化合物3和它的右手侧链，从而发现了各种新的烟碱配体，保留生物活性和功能改进的化学稳定性。与母体化合物4相比，最有前途的化合物24、26和30表现出相当或增强的药理学特征，并且N-甲基吡咯烷类似物26在小鼠强迫游泳试验中也表现出稳健的抗抑郁样功效。有利的ADMET特征和26的化学稳定性进一步表明该化合物是一种有前途的先导药物候选物，有助于药物发现管道的进一步发展。
A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds 24, 26, and 30 demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.
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影响因子：
--
作者：
Lynch, JK;Holladay, MW;King, SA
通讯作者：
King, SA
影响因子：
5.8
作者：
Quik M;Perez XA;Grady SR
通讯作者：
Grady SR
影响因子：
3.6
作者：
McIntosh, JM;Azam, L;Whiteaker, P
通讯作者：
Whiteaker, 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：
17.7
作者：
Trivedi, MH;Rush, AJ;Fava, M
通讯作者：
Fava, M