P-11 Nonomureae属放線菌の生産する新規グリシントランスポーター阻害剤の構造と活性(ポスター発表の部)

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N-methyl-D-aspartate (NMDA) receptor blockers have known to induce schizophrenic-like symptoms (both positive and negative symptoms) in humans. Thus, a dysfunction of glutamatergic transmission may play an important role in the pathophysiology of schizophrenia (hypoglutamatergic hypothesis). Glycine has been known to act as a requisite co-agonist of glutamate for activation of NMDA receptor. Levels of synaptic glycine are controlled by glycine transporter-1 (GlyT1) on glial cells. Therefore, the blockers of GlyT1 are expected to be antipsychotics. During the course of our screening program for novel GlyT1 inhibitors from natural origin, novel cyclic tetrapeptides (1〜6) were isolated from the fermentation broth of Nonomureae sp. H06075. The analysis of physicochemical and spectral data revealed that 1 was constructed with phenylalanine, two isoleucines and 4-oxo-3'-sulfoisoleucine. The structures of 2〜6 were also determined by comparison of their spectral data with those of 1. The absolute stereochemistries of amino acids were determined by advanced Marfey's method and chemical degradation. 1〜6 showed potent and selective inhibitory activity against GlyT1 on glial cells. The activities of synthetic cyclic pentapeptide, hexapeptide and liner tetrapeptide decreased significantly. Thus, cyclic tetrapeptide structure plays an important role in biological activity.
2006-09-15