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: 7899874
• 负责人: TAMAS BARTFAI
• 金额: $ 94.47万
• 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/7899874
• 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; 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; Treatment Protocols; 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.

神经毒气，如沙林和梭曼，被列为大规模杀伤性武器。暴露于 有机磷酸盐神经毒气（OP-NG），在战场上或通过恐怖行动，如东京 地铁事故，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 癫痫导致严重的脑损伤在这个建议中，我们的目标是发展有力的小说， 用于治疗OP-NG诱导的癫痫发作的抗惊厥药。这将通过针对两个 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，我们着手 三种独立的方法：目标概况如下：对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50倍于其它GPCR和离子通道的选择性， 参与控制癫痫发作、快速起效、OP-NG后应用时的抗惊厥活性 暴露，并且没有心血管或呼吸系统副作用和低药物相互作用可能性。化学 这个项目的出发点是很好的，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作用 模型，当化合物被系统地应用时。Gal-R1和Gal-R2的成功开发 激动剂不仅能提供一种对付恐怖主义威胁的强有力的反措施， 癫痫发作/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， 个人和平民免受OP-NG暴露的影响。