Badio B, Garraffo H M, Plummer C V, Padgett W L, Daly J W
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Eur J Pharmacol. 1997 Feb 26;321(2):189-94. doi: 10.1016/s0014-2999(96)00939-9.
Synthetic (+/-)-epiboxidine (exo-2-(3-methyl-5-isoxazolyl)-7-azabicyclo[2.2.1]heptane) is a methylisoxazole analog of the alkaloid epibatidine, itself a potent nicotinic receptor agonist with antinociceptive activity. Epiboxidine contains a methylisoxazolyl ring replacing the chloropyridinyl ring of epibatidine. Thus, it is also an analog of another nicotinic receptor agonist, ABT 418 ((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole), in which the pyridinyl ring of nicotine has been replaced by the methylisoxazolyl ring. Epiboxidine was about 10-fold less potent than epibatidine and about 17-fold more potent than ABT 418 in inhibiting [3H]nicotine binding to alpha 4 beta 2 nicotinic receptors in rat cerebral cortical membranes. In cultured cells with functional ion flux assays, epiboxidine was nearly equipotent to epibatidine and 200-fold more potent than ABT 418 at alpha 3 beta 4(5) nicotinic receptors in PC12 cells. Epiboxidine was about 5-fold less potent than epibatidine and about 30-fold more potent than ABT 418 in TE671 cells with alpha 1 beta 1 gamma delta nicotinic receptors. In a hot-plate antinociceptive assay with mice, epiboxidine was about 10-fold less potent than epibatidine. However, epiboxidine was also much less toxic than epibatidine in mice.
合成的（±）-表氧化苦参碱（外型-2-（3-甲基-5-异恶唑基）-7-氮杂双环[2.2.1]庚烷）是生物碱表小檗碱的甲基异恶唑类似物，表小檗碱本身是一种具有抗伤害感受活性的强效烟碱受体激动剂。表氧化苦参碱含有一个甲基异恶唑环，取代了表小檗碱的氯吡啶环。因此，它也是另一种烟碱受体激动剂ABT 418（（S）-3-甲基-5-（1-甲基-2-吡咯烷基）异恶唑）的类似物，其中尼古丁的吡啶环已被甲基异恶唑环取代。在抑制大鼠大脑皮层膜中[3H]尼古丁与α4β2烟碱受体结合方面，表氧化苦参碱的效力比表小檗碱低约10倍，比ABT 418高约17倍。在具有功能性离子通量测定的培养细胞中，在PC12细胞的α3β4（5）烟碱受体处，表氧化苦参碱与表小檗碱的效力几乎相当，比ABT 418高200倍。在具有α1β1γδ烟碱受体的TE671细胞中，表氧化苦参碱的效力比表小檗碱低约5倍，比ABT 418高约30倍。在小鼠的热板抗伤害感受试验中，表氧化苦参碱的效力比表小檗碱低约10倍。然而，表氧化苦参碱在小鼠中的毒性也比表小檗碱小得多。
