Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity.
Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity.
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DOI：
10.1021/jm201301h
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发表时间：
2012-01-26
影响因子：
7.3
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
--
作者：
Yu, Li-Fang;Tueckmantel, Werner;Eaton, J. Brek;Caldarone, Barbara;Fedolak, Allison;Hanania, Taleen;Brunner, Dani;Lukas, Ronald J.;Kozikowski, Alan P.
有相当多的证据支持这一假设，nAChR的阻断是负责烟碱配体的抗抑郁作用。烟碱乙酰胆碱受体（nAChR）拮抗剂美加明已被证明是对选择性5-羟色胺再摄取抑制剂无反应的患者的有效添加剂。这表明nAChR配体可以通过缓解难治性患者的抑郁症状来解决未满足的临床需求。在这项研究中，一个新的系列的nAChR配体的基础上的异恶唑醚支架已被设计和合成的结合和功能测定。初步的结构-活性关系（SAR）工作鉴定了先导化合物43，其在经典小鼠强迫游泳试验中具有有效的抗抑郁样活性（1 mg/kg，IP; 5 mg/kg，PO）。早期吸收、分布、代谢、排泄和毒性（ADME-Tox）研究也表明有利的药物样性质，并且对其他常见神经递质受体的广泛筛选表明化合物43对nAChR的选择性高于所测试的其他45种神经递质受体和转运蛋白。
There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening towards other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.
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影响因子：
10.6
作者：
Caldarone, BJ;Harrist, A;Picciotto, MR
通讯作者：
Picciotto, MR
影响因子：
2.7
作者：
ELLIOTT, RL;RYTHER, KB;GARVEY, DS
通讯作者：
GARVEY, DS
影响因子：
3.6
作者：
Eaton, JB;Peng, JH;Lukas, RJ
通讯作者：
Lukas, RJ
影响因子：
7.3
作者：
GARVEY, DS;WASICAK, JT;ARNERIC, SP
通讯作者：
ARNERIC, SP
影响因子：
5.8
作者：
Gotti, Cecilia;Clementi, Francesco;Zoli, Michele
通讯作者：
Zoli, Michele