DISUBSTITUTED GUANIDINES--NEW CLASS OF NEUROPRO DRUGS

THE GOAL OF THIS PROJECT IS TO PROVIDE A TREATMENT FOR NEUROLOGICAL CONDITIONS, SUCH AS EPILEPSY, STROKE, TRAUMA, AND A NUMBER OF NEURODEGENERATIVE DISEASES, THAT INVOLVE, OR ARE CAUSED BY, EXCESSIVE EXCITATION OF NERVE CELLS BY AGONISTS OF THE NMDA SUBTYPE OF GLUTAMATE RECEPTORS. EXPERIMENTS HAVE DEMONSTRATED THAT CERTAIN N,N'-DISUBSTITUTED GUANIDINES BIND TO THE PCP RECEPTOR ASSOCIATED WITH THE NMDA RECEPTOR, BLOCK THE ION CHANNEL OF THE NMDA RECEPTOR, AND CAN PROTECT NERVE CELLS FROM GLUTAMATE-INDUCED CELL DEATH IN BOTH IN VITRO AND IN VIVO MODELS. IN PHASE I OF THIS PROJECT, SECOND-GENERATION N,N'-DISUBSTITUTED GUANIDINES WILL BE SYNTHESIZED AND TESTEDFOR THEIR ABILITY TO: (1) INHIBIT BINDING TO THE PCP RECEPTOR IN RAT BRAIN MEMBRANES, (2) BLOCK NMDA-ACTIVATED ION CHANNELS ON CULTURED RAT BRAIN NEURONS, (3) PREVENT THE GLUTAMATE-INDUCED DEATH OF NEURONS IN AN IN VITRO SYSTEM, AND (4) REDUCE EXCITOTOXIN-INDUCED OR ANOXIA/ISCHEMIA-INDUCED NEURONAL DEGENERATION IN ANIMALS WHEN ADMINISTERED SYSTEMICALLY. LEAD NEUROPROTECTIVE COMPOUNDS WILL BE SELECTED BY THIS SCREENING PROCEDURE. PHASE II WILL INVOLVE THE SCALE-UP SYNTHESIS OF THESE COMPOUNDS AND INVESTIGATIONS OF THEIR EFFICACY IN FURTHER ANIMAL MODELS OF NEUROLOGICAL DISORDERS, TOXICITY, AND BIOAVAILABILITY.