DESCRIPTION: (Verbatim from the Applicant's Abstract) The pharmaceutical treatment of stroke and head trauma has been an elusive goal. Recent studies suggest that blockade of the AMPA class of glutamate receptors may limit neuronal degeneration following stroke/neurotrauma by blocking the excitotoxic cascade ultimately leading to cell death. Noncompetitive AMPA receptor antagonists show promise as neuroprotective drugs, and one such compound, GYKI 52466, is active in animal models of stroke. Based on structural modification of GYKI 52466, the applicants have synthesized Co 200010 which they claim to be the most potent noncompetitive AMPA receptor antagonist reported to date. In Phase I we will test whether Co200010 reduces cortical infarct size in a rat transient focal ischemia model. We will synthesize 10-20 analogs of Co200010 to improve critical determinants of therapeutic utility including potency, water solubility and bioavailability. After evaluating these compounds for potency and bioavailability by electrophysiological and behavioral assays, we will choose one or two of the best analogs for further testing in the ischemia studies. In Phase II we will evaluate additional compounds, test potential development leads in additional stroke models. And identify the best two compounds as preclinical development candidates. The foal of this project is to discover a noncompetitive AMPA receptor antagonist for the treatment of stroke and head trauma. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE