Carroll F Ivy
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Heterocycles. 2009;79:99-120. doi: 10.3987/rev-08-sr(d)1.
In 1992 Daly and co-workers reported the isolation of a new natural product, epibatidine. Future studies showed that epibatidine was an nAChR ligand with analgesic potency 200-400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine's unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the α4β2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction.
1992年，戴利及其同事报告了一种新天然产物——埃皮巴蒂丁的分离。后续研究表明，埃皮巴蒂丁是一种烟碱型乙酰胆碱受体（nAChR）配体，其镇痛效力比吗啡高200至400倍。然而，其作为一种新药的潜力受到其毒副作用的限制，这可能是由于它对多种nAChR亚型具有活性所致。埃皮巴蒂丁独特的结构和强大的活性使其成为开发副作用减少且nAChR亚型选择性更好的nAChR配体的理想先导结构。本综述介绍了我们用于合成多种埃皮巴蒂丁激动剂、拮抗剂以及混合激动剂/拮抗剂的合成方法，以便更好地表征α4β2 nAChR药效团，并有望提供具有治疗尼古丁成瘾潜力的化合物。
