著者

秋元 隆史 篠原 涼子 岩本 理 山下 まり 山岡 薫 長澤 和夫

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.53, pp.517-522, 2011

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Voltage-gated sodium channels (Na_vCh) are transmembrane proteins that provide inward current carried by sodium ions, and they contribute to the control of membrane excitability, as well as the propagation of action potentials along axons. To date, nine subtypes of sodium channels (NaChs) have been identified, which are closely related to life activity such as a sense of pain, a heartbeat, the muscle expansion and contraction. Since each of these subtypes has unique properties, subtype selective ligand is required for controlling and elucidation of these functions. Saxitoxin (STX) is a naturally occurring NavCh inhibitor, which is believed to bind to the P-loop region of the ion-selective filter in NavCh, and blocks ion influx of Na_vChs in a similar manner to tetrdotoxin (TTX). Recently, a binding model of STX with P-loop domain was proposed based on molecular docking studies by Zhorov. From this model, domain I and STX in C13 and N7 is crucial for the interaction. In this paper, we described the structure-activity relationship studies on STX derivatives with focusing on the C13 and N7 positions. New STX derivatives of 14, 16-18, 23 and 24 modified at C13 and N7 were synthesized from fully protected form of STX of 8 efficiently. Inhibitory activity of these new derivatives against Na_vChs, i.e., Na_v1.2, Na_v1.4 (these are TTX-sensitive) and Na_v1.5 (TTX-resistant), were evaluated by the who'e-cell patch clamp method. As shown in Table 1, these derivatives show moderate inhibitory activities against Na_v1.2, Na_v1.4, but no inhibitory activity was observed to Na_v1.5. Further SAR studies are in progress.