Lacosamide isothiocyanate-based agents: novel agents to target and identify lacosamide receptors.
Lacosamide isothiocyanate-based agents: novel agents to target and identify lacosamide receptors.
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拉科酰胺异硫氰酸酯类药物：靶向和识别拉科酰胺受体的新型药物。
DOI：
10.1021/jm9012054
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发表时间：
2009
影响因子：
7.3
通讯作者：
Kohn,Harold
中科院分区：
文献类型：
--
作者：
Park,KiDuk;Morieux,Pierre;Salomé,Christophe;Cotten,StevenW;Reamtong,Onrapak;Eyers,Claire;Gaskell,SimonJ;Stables,JamesP;Liu,Rihe;Kohn,Harold
(R)-拉科酰胺((R)-2，(R)-N-苄基-2-乙酰氨基-3-甲氧基丙酰胺)最近获得监管部门批准，用于治疗成人部分发作。全动物药理研究证明，(R)-2的功能是独特的。通过使用含有“亲和诱饵(AB)”和“化学报告(CR)”官能团的(R)-2类似物3，提出了一种发现与(R)-2功能和毒性相关的相互作用蛋白的强有力的策略。在3中，相互作用蛋白的共价修饰在AB部分进行，当与适当的探针反应时，通过生物正交CR基团进行选择性捕获蛋白的检测或分离。我们报道了利用3个AB基团为异硫氰酸酯基团的小鼠可溶脑蛋白质组的合成、药理评价和询问。其中一种化合物(R)-N-(4-异硫氰酸苄基)2-乙酰氨基-3-(丙基-2-乙酰氧基)丙酰胺((R)-9)在小鼠中表现出良好的抗癫痫作用，与(R)-2一样，抗惊厥活性主要存在于(R)-立体异构体中。与(S)-9相比，(R)-9优先标记了几个蛋白质，包括崩解素反应介质蛋白2。
(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide) has recently gained regulatory approval for the treatment of partial-onset seizures in adults. Whole animal pharmacological studies have documented that (R)-2function is unique. A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2through the use of (R)-2analogues,3, which contain “affinity bait (AB)” and “chemical reporter (CR)” functional groups. In3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with an appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using3where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-9), exhibited excellent seizure protection in mice, and like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9compared with (S)-9, including collapsin response mediator protein 2.