Developing GalR1/2 Agonists to Treat Nerve Gas Induced Seizure

点击翻译按钮获取中文摘要

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.