取代二苯酮Schiff碱型γ-氨基丁酸酯类化合物的抗惊厥活性研究

Anticonvulsant Activity of 4- [(Chlorophenyl) (5-Fluro-2-HydroxyPhenyl) Methylene Amino] Butyrates

作者以脑内γ-氨基丁酸(GABA)受体为靶,设计并合成了8个4-(4-氯苯基)(5-氟-2-羟基苯基)亚甲氨基]丁酸酯类化合物。所合成的化合物均未见文献报道。采用美国NIH提出的“抗癫痫药物开发程序”(ADD)对所合成的化合物进行抗惊厥活性筛选。结果表明有两个化合物具有抗癫痫活性。其中4-[4-氯苯基)(5-氟-2-羟基苯基)亚甲氨基]丁酸环己酯有进一步研究的价值。

γ-aminobutyric acid (GABA) is a major inhibitory transmitter in the cen- tral nervous system of animals and man. Most studics indicatcd that GABA plays a rolc in the pathophysiology ef cpilepsy. GABA insrcases the threshold of convulsion when it was administered locally in the brain of dog. Under physiological condition GABA poorly crosscs the blood-brain barrier, so it is not effective when administered orally. It is likely that a nontoxic GABA mimetic which easily entcrs the brain will have useful therapeutic properties. With this in mind, we have designed and synthesized 8 derivatives of γ-amino- butyric acid with an imine link (Schiff basc) to a lipophilc carrier in order to facilitate the passagc of γ-aminobutyric acid across the blood-brain barrier (IVa-Ivh). The synthesized 8 title compounds were evaluated as antico- nvulsants in mice via the anticpilelic drug development program of NIH. Compounds Ivb, Ivf showed anticonvulsant activity.