Jefferies P R, Gengo P J, Watson M J, Casida J E
Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720-3112, USA.
J Med Chem. 1996 Jun 7;39(12):2339-46. doi: 10.1021/jm950712d.
Ryanodine (1) and dehydroryanodine (2) are equipotent probes for the ryanodine receptor (ryr) of calcium release channels and differ only in 9eq-methyl for 1 and 9,21-methylene for 2. Ryanoids 1 and 2 are used here to prepare novel modifications of the cyclohexane substituents to determine their effects on ryr activity and selectivity. 10-Oxo-1 when reacted with carbonyl and other reagents gave 13 C-10 derivatives including the epi-amine and epi-4-azidobenzoyl hydrazide as a candidate affinity probe. Four derivatives of 2 including the delta 8-10-hydroxy and delta 8-10-oxo compounds. Defunctionalization of the cyclohexane ring of 2 or its 4,6-ethylboronate was achieved in part by controlled periodate oxidation of the 9,21-diol to the 21-nor-9-oxo compounds. These in turn provided access to the 9ax- and 9eq-hydroxy derivatives and to the 21-nor-10-deoxy-9-oxo compound which was converted to 21-nor-10-deoxy-1 and 10-deoxy-2 along with the epimeric 10-deoxy-9-hydroxy compounds. Ryanoids of similar potency to 1 as inhibitors of [3H]-1 binding in mouse brain, rabbit skeletal muscle, and canine ventricle ryr preparations and in rat cardiac contractility assay (inhibition of mechanical response to electrical stimulation) are epi-1 and the 10-epi-amino, 10-epi-methoxyamino, and 10-epi-azidobenzoyl hydrazide derivatives and 10-deoxydehydroryanodine. With a few exceptions the potency of the ryanoids at the cardiac ryr correlates well with their inhibition of cardiac contractility, indicating that the activity is associated with stabilizing the calcium release channel in a subconducting state, thereby uncoupling the excitation-contraction process.
ryanodine（1）和去氢ryanodine（2）是钙释放通道ryanodine受体（ryr）的等效探针，仅在1的9位甲基和2的9,21位亚甲基上有所不同。在此使用ryanoids 1和2制备环己烷取代基的新型修饰物，以确定它们对ryr活性和选择性的影响。10-氧代-1与羰基及其他试剂反应生成了13C-10衍生物，包括表胺和表-4-叠氮苯甲酰肼作为候选亲和探针。2的四种衍生物，包括δ8-10-羟基和δ8-10-氧代化合物。2的环己烷环或其4,6-硼酸乙酯的去官能化部分是通过将9,21-二醇用高碘酸盐控制氧化为21-降-9-氧代化合物来实现的。这些化合物进而提供了获得9轴向和9平伏羟基衍生物以及21-降-10-脱氧-9-氧代化合物的途径，该化合物被转化为21-降-10-脱氧-1和10-脱氧-2以及差向异构的10-脱氧-9-羟基化合物。在小鼠脑、兔骨骼肌和犬心室ryr制剂以及大鼠心脏收缩性测定（抑制对电刺激的机械反应）中，作为[3H]-1结合抑制剂，与1效力相似的ryanoids有表-1以及10-表-氨基、10-表-甲氧基氨基和10-表-叠氮苯甲酰肼衍生物以及10-脱氧去氢ryanodine。除了少数例外，ryanoids在心脏ryr上的效力与其对心脏收缩性的抑制作用相关性良好，表明该活性与将钙释放通道稳定在亚传导状态有关，从而使兴奋-收缩过程解偶联。
