Merging the structural motifs of functionalized amino acids and alpha-aminoamides: compounds with significant anticonvulsant activities.
Merging the structural motifs of functionalized amino acids and alpha-aminoamides: compounds with significant anticonvulsant activities.
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合并功能化氨基酸和 α-氨基酰胺的结构基序：具有显着抗惊厥活性的化合物。
DOI：
10.1021/jm100185c
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发表时间：
2010
影响因子：
7.3
通讯作者：
Kohn,Harold
中科院分区：
文献类型：
--
作者：
Salome,Christophe;Salome-Grosjean,Elise;Stables,JamesP;Kohn,Harold
功能性氨基酸 (FAA) 和 α-氨基酰胺 (AAA) 是两类具有显着抗惊厥活性的抗癫痫药物 (AED)。我们结合了 FAA 和 AAA 中存在的关键结构药效团，生成了一系列新的化合物，并记录了所选化合物在大鼠最大电击 (MES) 癫痫模型中表现出优于原型 FAA（拉科酰胺）或原型 AAA（沙芬酰胺）的活性。代表性化合物 (R)-N-4'-((3''-氟)苄氧基)苄基 2-乙酰氨基-3-甲氧基丙酰胺 ((R)-10) 在 MES（小鼠，ip）、MES（大鼠，po）、精神运动 6 Hz（32 mA）（小鼠，ip）和海马点燃（大鼠，ip）癫痫测试中进行了测试，提供了出色的保护和 ED50 值分别为 13、14、~10 mg/kg 和 12 mg/kg。在大鼠坐骨神经结扎模型 (ip) 中，(R)-10(12 mg/kg) 使机械异常性疼痛减弱 11.2 倍。在小鼠双相福尔马林疼痛模型 (ip) 中，(R)-10(15 mg/kg) 减轻了急性和慢性炎症阶段的疼痛反应。
Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3′′-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50values of 13, 14, ∼10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10(12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10(15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.