Nerve gases, such as sarin and soman, are classified as weapons of mass destruction. Exposure toorganophosphate nerve gases (OP-NG), on the battle field or through terrorist actions like the Tokyosubway incident, leads to convulsions, respiratory failure, and ultimately death. Current prophylaxis andtherapy regimen are not effective for OP-NG induced seizures, which usually progress rapidly into statusepilepticus, causing profound brain damage. In this proposal, we aim at the development of potent novelanticonvulsants for the treatment of OP-NG induced seizures. This will be achieved by targeting twoG-protein coupled receptors (GPCR) in the central nervous system, Gal-R1 and Gal-R2. Both Gal-R1 andGal-R2 are receptors for the neuropeptide galanin and are expressed at high levels in the hippocampus ofthe rodent brain. Preclinical studies have shown that signaling through these two galanin receptor subtypesmediates potent anticonvulsant actions. In order to develop potent Gal-R1 and Gal-R2 agonists we embarkon three independent approaches: The target profile is as follows: double digit nanomolar affinity for Gal-R1and or Gal-R2 receptors, agonist activity, at least 50 fold selectivity over other GPCRs and ion channels thatare involved in the control of seizure, rapid onset of action, anticonvulsant activity when applied after OP-NGexposure, and no cardiovascular or respiratory side effect and low drug interaction potential. The chemicalstarting points of this project are excellent as we have already obtained several Gal-R1 and Gal-R2 ligandsand our in vivo experiments demonstrate the anticonvulsant potency of these compounds in several seizuremodels, when the compounds are applied systemically. Successful development of Gal-R1 and Gal-R2agonists will not only provide a powerful countermeasure against the terrorist threat but also could bring anew treatment mechanism for seizure/epilepsy.Seizure is a fatal consequence following nerve gas exposure. Counter-terrorist measures proposed hereinclude the identification and development of a novel and potent anticonvulsant agent to protect militarypersonal and civilians from the effect of OP-NG exposure.
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