Developing GalR 1/2 Agonists to Treat Nerve Gas Induced Seizure

描述（由申请人提供）： 神经毒气，如沙林和梭曼，被列为大规模杀伤性武器。在战场上或通过恐怖行动（如东京地铁事件）暴露于有机磷酸盐神经毒气（OP-NG）会导致抽搐，呼吸衰竭，最终死亡。目前的预防和治疗方案对OP-NG诱导的癫痫发作无效，癫痫发作通常迅速进展为癫痫持续状态，导致严重的脑损伤。在这项提案中，我们的目标是开发有效的新型抗惊厥药，用于治疗OP-NG诱导的癫痫发作。这将通过靶向中枢神经系统中的两种G蛋白偶联受体（GPCR）Gal-R1和Gal-R2来实现。Gal-R1和Gal-R2都是神经肽甘丙肽的受体，并且在啮齿动物脑的海马体中以高水平表达。临床前研究表明，通过这两种甘丙肽受体亚型的信号传导介导了有效的抗惊厥作用。为了开发有效的Gal-R1和Gal-R2激动剂，我们开始采用三种独立的方法：对Gal-R1和/或Gal-R2受体的两位数纳摩尔亲和力、激动剂活性、超过参与控制癫痫发作的其它GPCR和离子通道的至少50倍选择性、快速起效、在暴露于OP-NG后应用时的抗惊厥活性，且无心血管或呼吸道副作用，药物相互作用可能性低。该项目的化学起点是极好的，因为我们已经获得了几种Gal-R1和Gal-R2配体，并且我们的体内实验证明了这些化合物在全身应用时在几种癫痫发作模型中的抗惊厥效力。Gal-R1和Gal-R2激动剂的成功开发不仅将为应对恐怖主义威胁提供强有力的对策，而且还可能为癫痫发作/癫痫带来新的治疗机制。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确定和开发一种新的、有效的抗惊厥剂，以保护军人和平民免受OP-NG暴露的影响。

DESCRIPTION (provided by applicant): 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.