The primary goal of this proposal is to develop a new class of calcium channel blocker that will act specifically at the neuronal N-type calcium channel. Agents that specifically block this channel are expected to inhibit the excessive release of various neurotransmitters which cause cell damage after ischemia. Two classes of lead molecules whose activity at the N-type calcium channel has been demonstrated (Phase I study) will be chemically modified with the goal of producing a high potency blocker of the channel. A human blood cell which has been shown to have functional N-type calcium channels will be further studied in an effort to develop a functional screen for the testing of newly synthesized agents. The agents to be synthesized will be evaluated in a radioreceptor binding assay, a glutamate release assay and in a cell culture neuroprotection assay with the goal of determining the functionality of the molecule. The synthesized agents will also be tested in animal models of seizures. Specific N-type calcium channel blockers are currently not available. Agents with activity at this site may prove to be medically important for the treatment of neurologic diseases such as epilepsy, stroke and neurodegenerative disease.
