DEVELOPMENT OF POTENT ACTIVE COMPOUNDS WORKING ON NEUROTRANSMIT ORGAN

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Among neurocells signals are transmitted by compounds called neurotransmitters. Glutamic acid is one of them and it is released from a fore-cell are and received by a receptor of a back-cell. This glutamate receptor is believed to play a role in the important functions such as memory and learning. Studies on the function of the receptor through organic synthesis have been achieved in this project.1) Acromelic acid B was synthesized in 21% orverall yield. It was acomplished by the intramolecular Diels-Alder addition of a enolate of an aromatic aldehyde formed by the irradiation of UV light to a doulbe bond conjugated to ester.2) Conformational analysis of L-2-(carboxycyclopropyl)glycine (CCG) was carried out. CCGs would be a probe to clear the conformational demand of the glutamate receptor to the substrate. Several 3'-substituted CCG analogues were synthesized and observed their biological activities and their conformational analysis were carried out spectroscopically. Spatial arrangem … More ent of the functional groups in the substrate was consequently recognized and new agonists were also developed.3) The conformational demand for the pi-electron plane of the C_4 side-chain of kainoid was investigated. X-ray and spectroscopic studies on the strongly active kainoids show the diagonal arrangement of the pi-electron plane and pyrrolidine ring. The compounds whose pi-electron plane has almost the same plane as pyrrolidine ring were synthesized this time. They are 3-aza-2, 8-dicarboxy-6-methylbicyclo[3.3.0] octane system containing a double bond around C_6 in exo or end positions. All of their biological activities depressed very much and it shows that the diagonal relationship between the pi-electron plane and pyrrolidine ring is required to show strong biological activity.4) A short step synthesis of aromatic kainoid was newly developed. It depends on the addition of a radical species generated from methyl malonate by oxidation with Mn(III) to 4-aryl-3-dehydroproline. The lactone from of 4-aryl-2-carboxymethyl-4-hydroxyproline was first produced and it was converted to arylkainoid through hydrogenolysis of C_4-hydroxyl group.5) Four stereoisomers of 2-carboxy-4-methylenecyclopentylglycine (CPG) were synthesized by the addtion of trimethylenemethane to 3-dehydroglutamic acid. Among them, only CPG-IV was biologically active as potent as kainic acid. Less