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ANTICONVULSANT ACTIVITY OF CARAMIPHEN ANALOGS

机译：卡拉米芬类似物的抗惊厥活性

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Caramiphen potently blocks maximal electroshock (MES)-induced seizures in mice and rats. The anticonvulsant mechanism has been hypothesized to be due to high-affinity binding to sigma recognition sites in brain. To study the structure-activity relationship for anticonvulsant activity of caramiphen we evaluated 8 analogs in MES-induced seizures in rats and also determined whether a correlation exists between anticonvulsant potency and a binding affinity. Some of the analogs potently inhibited sigma binding but were devoid of anticonvulsant activity. Aminocaramiphen 2 (ED(50) = 3.4 mg/kg) and N-methyl-4-piperidinyl 1-phenylcyclopentanecarboxylate 9 (ED(50) = 4.8 mg/kg) showed anticonvulsant activity comparable to caramiphen (ED(50) = 3.1 mg/kg), although in sigma binding assays the affinities were 3-and 30-fold less than caramiphen, respectively. In the presence of 250 mu M of phenytoin, caramiphen and p-aminocaramiphen showed 3- to 5-fold increases in affinity for [H-3](+)pentazocine binding, whereas p-iodocaramiphen, which was inactive as an anticonvulsant, showed no change in affinity for sigma binding. These results indicate that anticonvulsant activity of the caramiphen analogs is not due to interaction with sigma binding sites. [References: 26]
机译：Caramiphen有效地阻止了小鼠和大鼠中最大的电击（MES）诱发的癫痫发作。假定抗惊厥机制是由于与大脑中sigma识别位点的高亲和力结合所致。为了研究卡那芬抗惊厥活性的构效关系，我们评估了MES诱导的大鼠癫痫发作中的8种类似物，并确定了抗惊厥药的效力与结合亲和力之间是否存在相关性。一些类似物有效抑制σ结合，但是没有抗惊厥活性。氨基苯甲酚2（ED（50）= 3.4 mg / kg）和N-甲基-4-哌啶基1-苯基环戊烷羧酸盐9（ED（50）= 4.8 mg / kg）的抗惊厥活性可媲美Caramiphen（ED（50）= 3.1 mg） / kg），尽管在sigma结合测定中，亲和力分别比对角胺小3倍和30倍。在存在250μM苯妥英的情况下，对苯二甲酰胺和对氨基苯甲酰胺对[H-3]（+）喷他佐辛结合的亲和力增加了3至5倍，而对β-碘对苯二甲酰胺却没有作为抗惊厥药的活性。对sigma绑定的亲和力没有变化。这些结果表明，Caramiphen类似物的抗惊厥活性不是由于与sigma结合位点的相互作用。 [参考：26]

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