Developing GalR1/2 Agonists to Treat Nerve Gas Induced Seizure

沙林和梭曼等神经毒气被归类为大规模杀伤性武器。暴露于 有机磷神经毒气(OP-NG)，在战场上或通过像东京这样的恐怖行动 地铁事故，导致抽搐、呼吸衰竭，最终死亡。当前的预防措施和 治疗方案对OP-NG诱导的癫痫发作无效，通常进展迅速。 癫痫，造成严重的脑损伤。在这项提议中，我们的目标是发展强有力的小说 抗惊厥药物治疗OP-NG致痫。这将通过以下两个目标来实现 中枢神经系统中的G蛋白偶联受体，Gal-R1和Gal-R2。Gal-R1和 GAL-R2是神经肽甘丙肽的受体，在大鼠海马区高水平表达。 啮齿动物的大脑。临床前研究表明，通过这两种甘丙素受体亚型发出的信号 调节强效的抗惊厥作用。为了开发有效的Gal-R1和Gal-R2激动剂，我们着手 关于三种独立的方法：靶向分布如下：Gal-R1的两位数纳摩尔亲和力 和或Gal-R2受体，激动剂活性，至少是其他GPCRs和离子通道选择性的50倍 参与控制癫痫发作，快速起效，在OP-NG后应用时具有抗惊厥活性 暴露，没有心血管或呼吸系统副作用，药物相互作用潜力低。化学物质 这个项目的起点很好，因为我们已经获得了几个Gal-R1和Gal-R2配体 我们的活体实验证明了这些化合物在几次癫痫发作中的抗惊厥效力 模型，当化合物被系统地应用时。Gal-R1和Gal-R2的研制成功 激动剂不仅将提供对抗恐怖主义威胁的强有力的对策，而且还可能带来 癫痫/癫痫的新治疗机制。 癫痫发作是神经毒气暴露后的致命后果。这里提出的反恐措施 包括鉴定和开发一种新的、有效的抗惊厥剂来保护军队 个人和平民免受OP-NG暴露的影响。

Nerve gases, such as sarin and soman, are classified as weapons of mass destruction. Exposure to organophosphate nerve gases (OP-NG), on the battle field or through terrorist actions like the Tokyo subway incident, leads to convulsions, respiratory failure, and ultimately death. Current prophylaxis and therapy regimen are not effective for OP-NG induced seizures, which usually progress rapidly into status epilepticus, causing profound brain damage. In this proposal, we aim at the development of potent novel anticonvulsants for the treatment of OP-NG induced seizures. This will be achieved by targeting two G-protein coupled receptors (GPCR) in the central nervous system, Gal-R1 and Gal-R2. Both Gal-R1 and Gal-R2 are receptors for the neuropeptide galanin and are expressed at high levels in the hippocampus of the rodent brain. Preclinical studies have shown that signaling through these two galanin receptor subtypes mediates potent anticonvulsant actions. In order to develop potent Gal-R1 and Gal-R2 agonists we embark on three independent approaches: The target profile is as follows: double digit nanomolar affinity for Gal-R1 and or Gal-R2 receptors, agonist activity, at least 50 fold selectivity over other GPCRs and ion channels that are involved in the control of seizure, rapid onset of action, anticonvulsant activity when applied after OP-NG exposure, and no cardiovascular or respiratory side effect and low drug interaction potential. The chemical starting points of this project are excellent as we have already obtained several Gal-R1 and Gal-R2 ligands and our in vivo experiments demonstrate the anticonvulsant potency of these compounds in several seizure models, when the compounds are applied systemically. Successful development of Gal-R1 and Gal-R2 agonists will not only provide a powerful countermeasure against the terrorist threat but also could bring a new treatment mechanism for seizure/epilepsy. Seizure is a fatal consequence following nerve gas exposure. Counter-terrorist measures proposed here include the identification and development of a novel and potent anticonvulsant agent to protect military personal and civilians from the effect of OP-NG exposure.