NOVEL GLUTAMATE RECEPTOR ANTAGONISTS FROM SPIDER VENOMS

THE EXCITATORY AMINO ACID (EAA) NEUROTRANSMITTERS, SUCH AS GLUTAMATE AND ASPARTATE, HAVE BEEN IMPLICATED IN THE PATHOLOGY OF A NUMBER OF NEUROLOGICAL DISORDERS, INCLUDING EPILEPSY, STROKE/ANOXIA, AND NEURODEGENERATIVE DISEASES. DRUGS THAT ANTAGONIZE EAA NEUROTRANSMISSION OFFER A NOVEL APPROACH TO TREATING THESE DISORDERS. THE GOAL OF THIS PROJECT IS TO ISOLATE NOVEL AND SPECIFIC GLUTAMATE RECEPTOR ANTAGONISTS FROM PREVIOUSLY UNCHARACTERIZED SPIDER VENOMS. SPIDERS ARE A GOOD POTENTIALSOURCE OF THERAPEUTICALLY USEFUL EAA RECEPTOR ANTAGONISTS BECAUSE THEIR VENOMS CONTAIN ANTAGONISTS OF THE GLUTAMATE RECEPTOR OF THE NEUROMUSCULAR JUNCTION OF THEIR INSECT PREY. PREVIOUS STUDIES SUGGEST THAT MANY SPIDER VENOMS CONTAIN ANTAGONISTS OF MAMMALIAN EAA RECEPTORS. IN PHASE I, SIX SPIDER VENOMS WILL BE FRACTIONATED BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AND SCREENED FOR NEUROACTIVE COMPONENTS. NEXT, THE MECHANISM OF ACTION OF THE ACTIVE COMPONENTS WILL BE DETERMINED USING ELECTROPHYSIOLOGICAL AND RECEPTOR-BINDING ASSAYS AS WELL AS AN IN VITRO EXCITOTOXICITY ASSAY. FINALLY, PRELIMINARY STRUCTURE ANALYSES WILL BE PERFORMED OF THOSE COMPOUNDS THATAPPEAR TO BE EAA RECEPTOR ANTAGONISTS. IN PHASE II, THE COMPLETE CHEMICAL STRUCTURE AND CHEMICAL SYNTHESIS ROUTE OF PROMISING COMPOUNDS WILL BE DETERMINED, AND FURTHER STUDIES OF THEIR IN VIVO EFFICACY, TOXIC EFFECTS, AND BIOAVAILABILITY WILL BE PERFORMED.