AMINOALKYLPYRIDINES: POTENT ORALLY ACTIVE ANTICONVULSANTS

STUDIES BY THE APPLICANT ON THE METABOLISM AND PHARMACOLOGY OF ADD17014, A NOVEL TRIAZOLINE ANTICONVULSANT, HAVE LED TO THE DISCOVERY OF THE AMINOAKYLHETEROCYCLES AS A UNIQUE CLASS OF ANTICONVULSANT AGENTS. INITIAL WORK ON AMINOALKYLPYRIDINES INDICATE THEY ARE NONTOXIC, AND HIGHLY EFFECTIVE BY THE ORAL ROUTE, WITH PROTECTIVE INDICES GREATER THAN 20. THEY IMPAIR PRESYNAPTIC RELEASE OF L-GLUTAMATE AND ALSO FUNCTION AS NONCOMPETITIVE NMDA ANTAGONISTS THAT INHIBIT WITH GREAT SELECTIVITY AND SPECIFICITY, THE SIGMA RECEPTOR, BUT SHOW NO AFFINITY FOR PCP RECEPTORS. NMDA RECEPTOR OVERSTIMULATION BY GLUTAMATE IS IMPLICATED IN EPILEPTOGENESIS AND EPILEPSY. THUS NMDA ANTAGONISTS WILL PROVIDE PROPHYLAXIS AND SEIZURE PROTECTION. THERE IS A DEFINITE NEED FOR SAFER, ORALLY ACTIVE NMDA ANTAGONISTS, TO AFFORD EFFECTIVE THERAPIES FOR THE EPILEPSIES. THE APPLICATION'S LONG-TERM OBJECTIVES ARE TO DEVELOP CLINICALLY USEFUL, NONTOXIC ANTIEPILEPTIC DRUGS FROM ANTICONVULSANT AMINOALKYL HETEROCYCLES BY RATIONAL ANALOGUE SYNTHESIS OF ACTIVE "LEADS" USING VARIOUS BASIC STRUCTURAL MODIFICATIONS. WE WILL INITIATE ANALOGUE SYNTHESIS OF LEAD AMINOALKYL-4-PYRIDINES, WHICH WILL INCLUDE TWO BASIC STRUCTURAL VARIATIONS. RESULTING DATA WILL BE USED TO GUIDE FURTHER ANALOGUE SYNTHESIS IN PHASE II. SYNTHETIC PROCEDURES HAVE BEEN DEVELOPED. EXCESSIVE LEVELS OF GLUTAMATE ARE SUSPECTED NOT ONLY IN EPILEPSY, BUT IN SEVERAL OTHER NEUROLOGICAL DISORDERS, E. G. STROKE. THUS, NONTOXIC, ORALLY ACTIVE NMDA ANTAGONISTS DEVELOPED FROM AMINOALKYLHETEROCYCLES, HAVE GOOD POTENTIAL FOR COMMERCIAL APPLICATION AS CLINICALLY USEFUL ANTI8EPILEPTIC DRUGS AND ALSO AS NEUROPROTECTIVE AGENTS IN OTHER NEUROLOGICAL DISORDERS.