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

开发 GalR 1/2 激动剂来治疗神经毒气引起的癫痫发作

• 批准号: 7899875
• 负责人: TAMAS BARTFAI
• 金额: $ 94.66万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899875
• 关键词: Developing; GalR; Agonists; Treat; Nerve

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.

描述（由申请人提供）： 沙林毒气和索曼毒气等神经毒气被归类为大规模杀伤性武器。在战场上或东京地铁事件等恐怖活动中接触有机磷神经毒气 (OP-NG) 会导致抽搐、呼吸衰竭，并最终死亡。目前的预防和治疗方案对于 OP-NG 诱发的癫痫发作无效，癫痫发作通常会迅速进展为癫痫持续状态，导致严重的脑损伤。在本提案中，我们的目标是开发有效的新型抗惊厥药来治疗 OP-NG 引起的癫痫发作。这将通过靶向中枢神经系统中的两个 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，在啮齿动物大脑的海马体中高水平表达。临床前研究表明，通过这两种甘丙肽受体亚型的信号传导可介导有效的抗惊厥作用。为了开发有效的 Gal-R1 和 Gal-R2 激动剂，我们采取了三种独立的方法：目标概况如下：对 Gal-R1 和/或 Gal-R2 受体的两位数纳摩尔亲和力、激动剂活性、比参与控制癫痫发作的其他 GPCR 和离子通道至少 50 倍的选择性、快速起效、OP-NG 暴露后应用时的抗惊厥活性，并且无心血管或心血管疾病 呼吸系统副作用和低药物相互作用潜力。该项目的化学起点非常好，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模型中的抗惊厥功效。 Gal-R1和Gal-R2激动剂的成功研发不仅将为应对恐怖主义威胁提供有力的对策，而且可能为癫痫/癫痫带来新的治疗机制。癫痫发作是接触神经毒气后的致命后果。这里提出的反恐措施包括识别和开发一种新型强效抗惊厥剂，以保护军人和平民免受 OP-NG 暴露的影响。

项目成果

Synthesis and biological evaluation of novel pyrimidine derivatives as sub-micromolar affinity ligands of GalR2.

作为 GalR2 亚微摩尔亲和配体的新型嘧啶衍生物的合成和生物学评价。

• DOI: 10.1016/j.bmcl.2011.09.033
• 发表时间: 2011
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Sagi,VasudevaNaidu;Liu,Tianyu;Lu,Xiaoying;Bartfai,Tamas;Roberts,Edward
• 通讯作者: Roberts,Edward