The endogenous neuropeptide galanin and its associated receptors galanin receptor 1 and galanin receptor 2 are highly localized in brain limbic structures and play an important role in the control of seizures in animal epilepsy models. As such, galanin receptors provide an attractive target for the development of novel anticonvulsant drugs. Our efforts to engineer galanin analogs that can penetrate the blood-brain-barrier and suppress seizures, yielded NAX 5055 (Gal-B2), a systemically-active analog that maintains low nanomolar affinity for galanin receptors and displays a potent anticonvulsant activity. In this report, we show that NAX 5055 is active in three models of epilepsy: 1) the Frings audiogenic seizure-susceptible mouse, 2) the mouse corneal kindling model of partial epilepsy, and 3) the 6 Hz model of pharmacoresistant epilepsy. NAX 5055 was not active in the traditional maximal electroshock and subcutaneous pentylenetetrazol seizure models. Unlike most antiepileptic drugs, NAX 5055 showed high potency in the 6 Hz model of epilepsy across all three different stimulation currents; i.e., 22, 32 and 44 mA, suggesting a potential use in the treatment of pharmacoresistant epilepsy. Furthermore, NAX 5055 was found to be biologically active after intravenous, intraperitoneal, and subcutaneous administration, and efficacy was associated with a linear pharmacokinetic profile. The results of the present investigation suggest that NAX 5055 is a first-in-class neurotherapeutic for the treatment of epilepsy in patients refractory to currently approved antiepileptic drugs.

中文翻译：

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开发新型抗癫痫药物：NAX 5055（一种全身活性甘丙肽类似物）在癫痫模型中的表征。


内源性神经肽甘丙肽及其相关受体甘丙肽受体1和甘丙肽受体2高度定位于大脑边缘结构，在动物癫痫模型的癫痫发作控制中发挥重要作用。因此，甘丙肽受体为新型抗惊厥药物的开发提供了一个有吸引力的靶点。我们努力设计能够穿透血脑屏障并抑制癫痫发作的甘丙肽类似物，产生了 NAX 5055 (Gal-B2)，这是一种全身活性类似物，可保持对甘丙肽受体的低纳摩尔亲和力，并显示出有效的抗惊厥活性。在本报告中，我们表明 NAX 5055 在三种癫痫模型中具有活性：1) Frings 听源性癫痫易感小鼠，2) 部分性癫痫的小鼠角膜点燃模型，以及 3) 耐药性癫痫的 6 Hz 模型。 NAX 5055 在传统的最大电击和皮下戊四氮癫痫发作模型中没有活性。与大多数抗癫痫药物不同，NAX 5055 在所有三种不同刺激电流的 6 Hz 癫痫模型中均表现出高效能；即 22、32 和 44 mA，表明其在治疗耐药性癫痫方面具有潜在用途。此外，NAX 5055 在静脉内、腹膜内和皮下给药后被发现具有生物活性，并且功效与线性药代动力学曲线相关。目前的研究结果表明，NAX 5055 是一种一流的神经治疗药物，用于治疗目前批准的抗癫痫药物难治性的癫痫患者。