Search for ryanodine binding inhibitor produced by microorganisms

ryanodine是一种植物生物碱，是ryanodine受体（RyR）的激动剂，具有杀虫活性。RyR是肌浆网的Ca^2+释放通道。哺乳动物的RyR有三种亚型：RyR 1、RyR 2和RyR 3。然而，昆虫有一个单一但不同的RyR。在从微生物代谢产物中筛选ryanodine结合抑制剂的过程中，我们从Penicillium sp. FKI-3795中分离到altenusin和dehydroaltenusin，从Nigrospora sp. FKI-3299中分离到CJ-13，982，从Penicillium sp. FKI-3647中分离到tenellic acid C。我们以前从Verticillium sp. FKI-1033的培养液中分离到一种新的24元环缩酚酸肽（24-memberedcyclopepsipeptide），命名为verticilide。平面结构已经研究，我们阐明了其水解产物的分析的绝对结构。我们还完成了它的全合成，并确认了结构。[^3H]标记的兰尼碱对蟑螂RyR和小鼠腿肌RyR的结合抑制作用<50>分别为4.2 μM<50>和53.9 μM。因此，它对蟑螂受体的抑制作用强约13倍。轮杀酯具有较好的杀虫杀螨活性。我们正在研究合成具有更强活性的轮枝环内酯类似物。

A plant alkaloid, ryanodine, is an agonist of ryanodine receptor (RyR) and exhibits insecticidal activity. RyR is a Ca^<2+> release channel of the sarcoplasmic reticulum. There are three subtypes, RyR1, RyR2, and RyR3, in mammalian RyR. However, insects have a single but distinct RyR. Therefore, insect RyR is a potential target for new insecticides.In the course of screening for ryanodine binding inhibitors from microbial metabolites, we isolated altenusin and dehydroaltenusin from PenicHlium sp. FKI-3795, CJ-13,982 from Nigrospora sp. FKI-3299, and tenellic acid C from Penicillium sp. FKI-3647. Their activities of ryanodine binding inhibition have not ever been reported.We have previously isolated a new 24-membered cyclic depsipeptide, named verticilide, from the culture broth of Verticillium sp. FKI-1033 as a ryanodine binding inhibitor. The planer structure was already studied, and we elucidated the absolute structure by the analysis of its hydrolysates. We have also accomplished its total synthesis and confirmed the structure. Verticilide exhibited [^3H]-labeled ryanodine binding inhibition against cockroach RyR at the IC_<50> value of 4.2 μM and against mouse leg muscle RyR at the IC_<50> value of 53.9 μM. Therefore, it showed about 13 times more potent inhibition to cockroach receptor. Verticilide showed some good insecticidal and acaricidal activities. We are studying the synthesis of verticilide analogs having much potent activity.