Fitch Richard W, Pei Xue-Feng, Kaneko Yumika, Gupta Tara, Shi Dan, Federova Irina, Daly John W
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Bioorg Med Chem. 2004 Jan 2;12(1):179-90. doi: 10.1016/j.bmc.2003.10.015.
Homoepiboxidine (3) and the corresponding N-methyl (4) and N-benzyl (5) derivatives were prepared from a 6beta-carbomethoxynortropane (8). Affinities and functional activities at neuromuscular, central neuronal and ganglionic-type nicotinic receptors were compared to those of epibatidine 1, and epiboxidine 2. Homoepiboxidine had equivalent affinity/activity to epiboxidine at neuromuscular, neuronal alpha4beta2, and most alpha3-containing ganglionic-type nicotinic receptors. The N-substituted derivatives showed reduced affinity/activity at most receptor subtypes. Replacement of the methylisoxazole moiety of 3 and 4 with a methyloxadiazole moiety provided analogues 6 and 7, which had greatly reduced affinity/activity in virtually all assays at nicotinic receptors. Marked analgetic activity in mice occurred at the following ip doses: epibatidine 10 microg/kg; epiboxidine 25 microg/kg; homoepiboxidine 100 microg/kg; N-methylhomoepiboxidine 100 microg/kg; the methyloxadiazole (6) 100 microg/kg. The time course at such ip doses was significantly longer for homoepiboxidine 3 with marked analgesia still manifest at 30 min post-injection. Epiboxidine and the homoepiboxidines were less toxic than epibatidine.
高表小檗胺（3）以及相应的N - 甲基（4）和N - 苄基（5）衍生物由6β - 甲氧羰基降托烷（8）制备而成。将它们在神经肌肉、中枢神经元和神经节型烟碱受体上的亲和力和功能活性与埃博霉素1和表小檗胺2进行了比较。高表小檗胺在神经肌肉、神经元α4β2以及大多数含α3的神经节型烟碱受体上具有与表小檗胺相当的亲和力/活性。N - 取代衍生物在大多数受体亚型上显示出降低的亲和力/活性。用甲基恶二唑部分取代3和4的甲基异恶唑部分得到类似物6和7，它们在几乎所有烟碱受体测定中的亲和力/活性都大大降低。小鼠腹腔注射后出现明显镇痛活性的剂量如下：埃博霉素10μg/kg；表小檗胺25μg/kg；高表小檗胺100μg/kg；N - 甲基高表小檗胺100μg/kg；甲基恶二唑（6）100μg/kg。高表小檗胺3在该腹腔注射剂量下的作用时间明显更长，注射后30分钟仍表现出明显的镇痛作用。表小檗胺和高表小檗胺的毒性低于埃博霉素。
