Developing GalR1/2 Agonists to Treat Nerve Gas Induced Seizure

开发 GalR1/2 激动剂来治疗神经毒气引起的癫痫发作

• 批准号: 8115053
• 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
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8115053
• 关键词: Acetylcholine; Adverse effects; Affect; Affinity; Agonist; Alkaloids; Alkylation; Anticonvulsants; Antidotes; Antiepileptogenic; Atropine; Attenuated; Belladonna; Blood - brain barrier anatomy; Brain; Brain Injuries; Cardiovascular system; Cells; Cessation of life; Characteristics; Chemicals; Chemistry; Clinical; Clonazepam; Convulsions; Data; Development; Digit structure; Drug Interactions; Drug Kinetics; Electroconvulsive Shock; Enzymes; Epilepsy; Event; Exposure to; G-Protein-Coupled Receptors; Galanin; Galnon; Gas Poisoning; Glutamates; Goals; Hilar; Hippocampus (Brain); Human Resources; In Vitro; Ion Channel; Lead; Left; Levetiracetam; Ligands; Lilium; Measures; Mediating; Military Personnel; Modeling; Molecular Models; Molecular Weight; Muscarinic Acetylcholine Receptor; Neuraxis; Neuropeptide Receptor; Organophosphates; Oximes; Pathology; Penetration; Personal Communication; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physostigmine; Pilocarpine; Poisoning; Prophylactic treatment; Publishing; Recruitment Activity; Regimen; Reporting; Respiratory Failure; Rodent; Sarin; Screening procedure; Seizures; Series; Signal Transduction; Site; Sodium; Soman; Status Epilepticus; Structure; Structure-Activity Relationship; Subway; Synapses; Testing; Tokyo; Toxicology; Vigabatrin; base; cheminformatics; cholinergic; esterase; felbamate; galactose receptor; galanin receptor; galmic; gamma-Aminobutyric Acid; high throughput screening; improved; in vivo; lead series; meetings; molecular modeling; nerve gas; neuroprotection; neurotransmission; novel; peptidomimetics; pre-clinical; preclinical study; presynaptic; receptor; research facility; research study; respiratory; standard care; tiagabine; transmission process; weapons of mass destruction

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.

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。接触 有机磷神经毒气 (OP-NG)，在战场上或通过东京等恐怖活动 地铁事件导致抽搐、呼吸衰竭，最终死亡。目前的预防措施和 治疗方案对 OP-NG 诱发的癫痫发作无效，癫痫发作通常会迅速进展为状态 癫痫，造成严重的脑损伤。在这个提案中，我们的目标是开发有效的小说 抗惊厥药用于治疗 OP-NG 引起的癫痫发作。这将通过瞄准两个目标来实现 中枢神经系统中的 G 蛋白偶联受体 (GPCR) Gal-R1 和 Gal-R2。 Gal-R1 和 Gal-R2 是神经肽甘丙肽的受体，在海马中高水平表达 啮齿动物的大脑。临床前研究表明，通过这两种甘丙肽受体亚型的信号传导 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，我们开始 三种独立方法：目标概况如下：Gal-R1 的两位数纳摩尔亲和力 和/或 Gal-R2 受体，激动剂活性，选择性比其他 GPCR 和离子通道至少高 50 倍 OP-NG 后应用时，参与控制癫痫发作、快速起效、抗惊厥活性 暴露，无心血管或呼吸系统副作用，药物相互作用潜力低。化学品 这个项目的起点非常好，因为我们已经获得了几个 Gal-R1 和 Gal-R2 配体 我们的体内实验证明了这些化合物在几种癫痫发作中的抗惊厥功效 模型，当化合物被系统地应用时。 Gal-R1和Gal-R2开发成功 激动剂不仅可以提供针对恐怖主义威胁的有力对策，而且可以带来 癫痫发作/癫痫的新治疗机制。 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 包括鉴定和开发一种新型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。