EXCITATORY AMINO ACID ANTAGONISTS AS ANTIEPILEPTIC DRUGS

THIS IS A PHASE I PROPOSAL WHERE FUNDING IS SOUGHT TO ASSIST IN THE SETTING UP OF A DRUG DISCOVERY AND DEVELOPMENT PROGRAM BY NOVA PHARMACEUTICAL CORPORATION LEADING TO NEW AND IMPROVED DRUGS TO TREAT EPILEPSY. ALTHOUGH THERE ARE CURRENTLY 16 MAJOR TYPES OF ANTIEPILEPTIC MEDICATIONS IN USE IN THE U.S., NONE HAS PROVEN COMPLETELY EFFECTIVE, AND MANY OF THE MOST COMMONLY PRESCRIBED COMPOUNDS GIVE RISE TO SIGNIFICANT AND PREVALENT ADVERSE SIDE EFFECTS. IT IS GENERALLY RECOGNIZED AT THE N.I.N.C.D.S. AND ELSEWHERE THAT THERE IS A CLINICAL NEED FOR NEW, MORE SELECTIVE AND EFFECTIVE, ANTIEPILEPTIC AGENTS. A VOLUME OF RECENT BASIC RESEARCH INDICATES THAT EPILEPSY MAY BE A NEURODEGENERATIVE PROCESS PRECIPITATED BY EXCESSIVE STIMULATION OF HIPPOCAMPAL OR TEMPORAL LOBE NEURONS, WITH SUBSEQUENT CELL DEATH. EXCITATORY AMINO ACIDS ACTING AT SPECIFIC RECEPTOR SITES HAVE BEEN IMPLICATED IN THIS PROCESS, INCLUDING "ENDOGENOUS BRAIN EXCITOTOXINS", SUCH AS QUINOLINIC ACID. DRUGS ACTING AS SPECIFIC ANTAGONISTS AT ONE OR MORE OF THE DISTINCT SUBTYPES OF EXCITATORY AMINO ACID RECEPTORS MAY HOLD PROMISE AS USEFUL AND EFFICACIOUS ANTI-EPILEPTIC AGENTS. ONE SUCH COMPOUND, (-)-2-AMINO-7-PHOSPHONOHEPTANOIC ACID (-APH) HAS ALREADY BEEN SHOWN TO POSSESS SIGNIFICANT ANTICONVULSANT ACTIVITY IN ANIMAL TESTS. WE PROPOSE TO INSTITUTE A PROGRAM TO DEVELOP AND SCREEN APH ANALOGUES TO ACHIEVE INCREASED POTENCY AND ORAL EFFICACY, LEADING ULTIMATELY TO CLINICAL TRIALS OF A LEAD COMPOUND. OVERALL, OUR PROGRAM WILL CONSIST OF CHEMICAL SYNTHESIS, SCREENING AT THE RECEPTOR LEVEL IN BINDING AND BIOCHEMICAL EXPERIMENTS (TO BE CORRELATED WITH ACTIVITY IN SIMPLE IN VIVO ANTICONVULSANT SCREENS), FOLLOWED BY MORE DETAILED RECEPTOR AUTORADIOGRAPHIC ANALYSIS, SINGLE UNIT ELECTROPHYSIOLOGY, AND EEG STUDIES, WITH PROMISING LEAD COMPOUNDS. SUBSEQUENTLY, ROUTINE TOXICOLOGIC AND BIOAVAILABILITY DETERMINATIONS WOULD BE UNDERTAKEN. INITIAL FUNDING (PHASE I) IS REQUESTED TO ESTABLISH THE CORRELATIVE RECEPTOR, BIOCHEMICAL AND BEHAVIORAL SCREENS FOR EXCITATORY AMINO ACID ANTAGONIST ACTIVITY IN -APH AND A SERIES OF ANALOGUES TO BE SYNTHESIZED BY US.