Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, United States.
J Med Chem. 2010 Dec 9;53(23):8345-53. doi: 10.1021/jm100994w. Epub 2010 Nov 8.
There is a need for different and better aids to tobacco product use cessation. Useful smoking cessation aids, bupropion (2) and varenicline (3), share some chemical features with 3-phenyltropanes (4), which have promise in cocaine dependence therapy. Here we report studies to generate and characterize pharmacodynamic features of 3-phenyltropane analogues. These studies extend our work on the multiple molecular target model for aids to smoking cessation. We identified several new 3-phenyltropane analogues that are superior to 2 in inhibition of dopamine, norepinephrine, and sometimes serotonin reuptake. All of these ligands also act as inhibitors of nicotinic acetylcholine receptor (nAChR) function with a selectivity profile that favors, like 2, inhibition of α3β4*-nAChR. Many of these ligands also block acute effects of nicotine-induced antinociception, locomotor activity, and hypothermia. Importantly, all except one of the analogues tested have better potencies in inhibition of nicotine conditioned place preference than 2. We have identified new compounds that have utility as research tools and possible promise for treatment of nicotine dependence.
需要不同的、更好的戒烟辅助工具。有用的戒烟辅助工具安非他酮（2）和伐尼克兰（3）与 3-苯丙基托烷（4）具有一些化学特征，后者在可卡因依赖治疗方面有前景。在这里，我们报告了生成和表征 3-苯丙基托烷类似物药效特征的研究。这些研究扩展了我们关于戒烟辅助工具的多分子靶模型的工作。我们确定了几种新的 3-苯丙基托烷类似物，它们在抑制多巴胺、去甲肾上腺素方面优于 2，并且有时在抑制 5-羟色胺再摄取方面也优于 2。所有这些配体也都作为烟碱型乙酰胆碱受体（nAChR）功能的抑制剂起作用，其选择性特征类似于 2，有利于抑制α3β4*-nAChR。这些配体中的许多还阻断了尼古丁诱导的镇痛、运动活动和体温降低的急性作用。重要的是，除了一个测试的类似物外，所有这些类似物在抑制尼古丁条件性位置偏好方面的效力都优于 2。我们已经确定了具有作为研究工具的实用性和治疗尼古丁依赖的潜在前景的新化合物。
