CROSS-AXIS COIL PLANET CENTRIFUGE CHROMATOGRAPH DESIGN AND SYNTHESIS OF BRAIN-SPECIFIC ANTIHERPETIC AGENTS

A NEW COUNTERCURRENT CHROMATOGRAPHY INSTRUMENT, THE CROSS-AXIS FLOW-THROUGH COIL PLANET CENTRIFUGE IS PROPOSED FOR THE PREPARATIVE CHROMATOGRAPHY OF PEPTIDES. THIS IS AN APPARATUS THAT SEPARATES SUBSTANCES ACCORDING TO THEIR PARTITIONING IN A LIQUID-LIQUID EQUILIBRATION SYSTEM WITHOUTTHE USE OF A SOLID-PHASE SUPPORT. THE INSTRUMENT WILL BE TESTED IN THE PURIFICATION OF LARGE QUANTITIES OF SYNTHETIC PEPTIDES, USING DIFFERENT CONDITIONS AND SOLVENT SYSTEMS TO ACHIEVE HIGH RESOLUTION AND RECOVERY. THE SUCCESSFUL DEVELOPMENT OF THIS INSTRUMENT WOULD MAKE AVAILABLE A LOWER COST TECHNOLOGY FOR CHROMATOGRAPHIC PURIFICATION. THE IMPEDIMENTS ENCOUNTERED IN THE TREATMENT OF HUMAN BRAIN ENCEPHALITIS HAVE SO FAR BEEN ATTRIBUTED TO THE INABILITY OFANTIVIRAL AGENTS TO REACH THE VIRAL SITE IN THE CNS. TO CIRCUMVENT THESE PROBLEMS UTILIZATION OF THE BRAIN-SPECIFIC CHEMICAL DELIVERY SYSTEM (ANALOGOUS TO THE NAD NADHREDOX SYSTEM) DEVELOPED BY BODOR AND ASSOCIATES IS PROPOSED. THIS SYSTEM IS BASED ON THE INTERCONVERSION OF LIPOPHILIC DIHYDROPYRIDINES WHICH READILY CROSS THE BBB BETWEEN HYDROPHILIC PYRIDINIUM SALTS WHICH ARE LOCKED IN THEBRAIN. THE ADVANTAGES OF THIS SYSTEM ARE 1) LOWER PERIPHERAL CONCENTRATIONS OF THE ACTIVE AGENT AND CONSEQUENTLY REDUCED SYSTEMIC TOXICITY 2) GREATER EFFICACY SINCE A LOWER DOSE CAN BE GIVEN TO ATTAIN CLINICALLY EFFECTIVE CEREBRAL CONCENTRATIONS. THE MAJOR AIM OF THIS PROPOSAL IS TO APPLY THE CHEMICAL DELIVERY SYSTEM TO SELECTED ANTIHERPETIC AGENTS. THE AREAS OF RESEARCH IN PHASE I WOULD INCLUDE SYNTHESIS OF DRUG-CARRIER SYSTEMS, DEVELOPMENT OF SUITABLE ANALYTICAL SYSTEMS, DETERMINATION OFSTABILITY IN VITRO USING VARIOUS MATRICES TO ESTABLISH THE RATE AT WHICH THE FREE DRUG IS RELEASED FROM THE CARRIER. EVALUATION OF THE LIPOPHILICITY AND NEUROTOXICITY OF DRUG-CARRIER SYSTEMS. IN PHASE II BASED ON THE RESULTS FROMPHASE I AT LEAST TWO COMPOUNDS WILL BE SELECTED FOR IN-DEPTH IN VIVO DISTRIBUTION AND ACTIVITY STUDIES.