Jefferies P R, Lehmberg E, Lam W W, Casida J E
Department of Entomological Sciences, University of California, Berkeley 94720.
J Med Chem. 1993 Apr 30;36(9):1128-35. doi: 10.1021/jm00061a003.
Ryanoids are the most potent inhibitors known for the calcium-release channel (ryanodine receptor), and they are also botanical insecticides. Twenty-two new ryanoids are described in which the C-4, C-12 bond is ruptured or replaced with an oxygen bridge and in which substituents at C-4 and C-12 are modified to have a wide range of polarities. They are obtained by nucleophilic additions to the 4,12-seco-4,12-dioxo compounds or diketones prepared from ryanodine and dehydroryanodine by periodate oxidation. Structures of the new compounds are distinguished by changes in NMR chemical shifts of 13C and 1H nuclei in the regions of C-4 and C-12. The new ryanoids are compared with ryanodine as inhibitors of [3H]ryanodine binding using a rabbit muscle sarcoplasmic reticulum preparation alone or with ATP and a mouse brain receptor with ATP. They are also examined as knockdown agents for houseflies pretreated with a cytochrome P450 oxidase inhibitor to suppress detoxification and then injection with the ryanoid. The diketones have very weak binding activity in the receptor assays and very low toxicity to flies. Activity approaching that of ryanodine in both the receptor and fly assays is obtained for ketals with small groups at C-12 and polar substituents such as OH or NHOH at C-4. The oximes range from low to moderate potency. Addition of thiols to the vinyl group of dehydroryanodine gives three thioethers all of low biological activity. With most ryanoids addition of ATP to the muscle system increases its sensitivity to near that found for the brain receptor with ATP; possible exceptions are compounds with phenyl substituents. Activity at the calcium-release channel generally follows housefly toxicity although the hydrazine and hydroxyamine adducts are much weaker than expected perhaps due to dissociation under the assay conditions.
鱼尼丁类化合物是已知对钙释放通道（鱼尼丁受体）最有效的抑制剂，它们也是植物源杀虫剂。本文描述了22种新的鱼尼丁类化合物，其中C-4、C-12键断裂或被氧桥取代，且C-4和C-12位的取代基经修饰后具有广泛的极性。它们是通过对由高碘酸盐氧化鱼尼丁和去氢鱼尼丁制备的4,12-开环-4,12-二氧代化合物或二酮进行亲核加成而得到的。新化合物的结构通过C-4和C-12区域中13C和1H核的NMR化学位移变化来区分。将新的鱼尼丁类化合物与鱼尼丁作为[3H]鱼尼丁结合的抑制剂进行比较，单独使用兔肌肌浆网制剂或与ATP一起使用，以及与ATP一起使用小鼠脑受体。它们还被用作击倒剂，用于先用细胞色素P450氧化酶抑制剂预处理以抑制解毒作用，然后注射鱼尼丁类化合物的家蝇。在受体测定中，二酮具有非常弱的结合活性，对苍蝇的毒性也非常低。对于在C-12位具有小基团且在C-4位具有极性取代基（如OH或NHOH）的缩酮，在受体测定和苍蝇测定中均获得了接近鱼尼丁活性的活性。肟类化合物的活性范围从低到中等。向去氢鱼尼丁的乙烯基添加硫醇得到三种硫醚，它们的生物活性都很低。对于大多数鱼尼丁类化合物，向肌肉系统中添加ATP会增加其敏感性，使其接近在有ATP存在时脑受体的敏感性；可能的例外是具有苯基取代基的化合物。钙释放通道的活性通常与家蝇毒性一致，尽管肼和羟胺加合物的活性比预期弱得多，这可能是由于在测定条件下发生了解离。
