Carroll F Ivy, Ware Roy, Brieaddy Lawrence E, Navarro Hernán A, Damaj M I, Martin Billy R
Chemistry and Life Sciences, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 2004 Aug 26;47(18):4588-94. doi: 10.1021/jm040078g.
A series of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues (5a-k) showed high affinity for alpha4beta2 binding with no affinity at alpha7 nAChRs. The most potent compound was 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (5g) which possessed a Ki value of 0.009 nM. Surprisingly, none of the compounds showed agonist effects in pain tests and body temperature changes in mice even when tested at 10-15 mg/kg with the exception of 5b, which showed only very weak agonist effects. In contrast, all the compounds were potent functional antagonists of nicotine-induced antinociception. Interestingly, the 3'-substituted phenyl analogues 5b-k were 10-870-fold more effective as antagonists in the tail-flick test versus the hot-plate procedure. They failed to antagonize nicotine-induced hypothermia. The 4-chlorophenyl analogue (5e) (AD50 = 0.0003 in the tail-flick test) was the most potent and selective analogue. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. These compounds also deserve consideration as potential pharmacotherapies for treatment of smoking cessation.
一系列2'-氟-3'-(取代苯基)去氯表鬼臼毒素类似物(5a-k)对α4β2具有高亲和力，而对α7烟碱型乙酰胆碱受体无亲和力。最有效的化合物是2'-氟-3'-(4-硝基苯基)去氯表鬼臼毒素(5g)，其Ki值为0.009 nM。令人惊讶的是，即使以10-15 mg/kg的剂量进行测试，除了仅表现出非常微弱激动作用的5b之外，没有一种化合物在小鼠的疼痛测试和体温变化中表现出激动作用。相反，所有化合物都是烟碱诱导的抗伤害感受的强效功能性拮抗剂。有趣的是，在甩尾试验中，3'-取代苯基类似物5b-k作为拮抗剂的效力比热板试验高10-870倍。它们未能拮抗烟碱诱导的体温过低。4-氯苯基类似物(5e)(甩尾试验中的AD50 = 0.0003)是最有效和选择性最高的类似物。这些结果表明，这些化合物对于确定每种烟碱药理作用涉及哪些特定受体亚型将非常有用。这些化合物也值得作为戒烟的潜在药物疗法加以考虑。
