Subtype-Selective Nicotinic Receptor Ligands as Smoking Cessation Pharmacotherapy

在世界许多地方，烟草使用是导致残疾和死亡的主要可预防原因。在联合 仅在美国，每年就有44万人死于吸烟引起的疾病，其中一半是长期吸烟。 吸烟者会死于与吸烟有关的疾病。吸烟有很强的依赖性，占70%， 吸烟者说他们想戒烟，但超过90%的人试图戒烟失败。对于大多数吸烟者来说， 尼古丁依赖是持续使用的。目前戒烟的药物治疗有 非选择性和最小有效性。因此，拟议申请的长期目标是 开发额外的、改进的药物疗法。为此，我们将首先测试假设， 烟碱乙酰胆碱受体的α 3 β 4亚型是尼古丁药物的合适靶点 受体拮抗剂可以减少尼古丁和其他药物的奖励方面 虐待尽管α 3 β 4拮抗剂已显示出减少尼古丁自我给药的功效 和其他滥用药物，但该位点没有已知的选择性拮抗剂。选择性和高亲和力配体 将设计的基础上的分子建模研究和发展的受体选择性 药效团还将探讨激动剂和拮抗剂活性的分子决定因素。 将在体外测试化合物对HEK细胞系的结合亲和力和功能活性，所述HEK细胞系具有 用α 3 β 4和α 4 β 2烟碱乙酰胆碱受体亚型转染。铅 将使用膜片钳电生理技术更仔细地检查化合物，以确定 活性是电压依赖性的还是活性依赖性的，并确定 受体。最后，将测试铅化合物，以确定它们是否能减弱尼古丁自身的毒性。 在小鼠中施用。因为α 3 β 4拮抗剂已经被声称可以阻断由 许多药物滥用，铅化合物也将进行测试，以确定他们是否减弱吗啡， 可卡因诱导的小鼠位置偏爱。 烟草使用是一个严重的公共卫生问题，没有很好的戒烟药物 目前可用。所发现的新型亚型选择性烟碱受体配体将可用作 用于更好地理解α 3 β 4烟碱受体在尼古丁中的作用的药理学探针 成瘾和奖励，并可以开发为潜在的戒烟药物。

Tobacco use is the primary preventable cause of disability and death in much of the world . In the United States alone, 440,000 people die each year from smoking-induced disease, and half of all long-term smokers will die of a smoking-related disease. Smoking has a powerful dependence component¿70% of smokers say they want to quit, but more than 90% of those who try fail to do so. For most smokers, tobacco use is sustained by nicotine dependence. Current pharmacotherapies for smoking cessation are nonselective and minimally effective. The long-term objectives of the proposed application are thus to develop additional, improved pharmacotherapies. To that end, we will first test the hypotheses that the alpha3beta4 subtype of the .nicotinic acetylcholine receptor is a suitable target for nicotine medication development, and that receptor antagonists can diminish the rewarding aspects of nicotine and other drugs of abuse. Although alpha3beta4 antagonists have shown efficacy in reducing self-administration of nicotine and other drugs of abuse, no selective antagonists are known for this site. Selective and high-affinity ligands will be designed on the basis of molecular modeling studies and development of a receptor-selective pharmacophore. Molecular determinants of agonist and antagonist activity will also be explored. Compounds will be tested in vitro for binding affinities and functional activities on HEK cell lines that have been transfected with the alpha3beta4 and the alpha4beta2 nicotinic acetylcholine receptor subtypes. Lead compounds will be examined more carefully using patch clamp electrophysiological techniques to determine whether activity is voltage- or activity-dependent and to determine the rate of desensitization of the receptors. Finally, lead compounds will be tested to determine whether they attenuate nicotine self- administration in mice. Because alpha3beta4 antagonists have been claimed to block the reward induced by many drugs of abuse, lead compounds will also be tested to detemine whether they attenuate morphine and cocaine-induced place preference in mice. Tobacco use is a serious public health problem with no good pharmacotherapies for smoking cessation currently available. The novel subtype-selective nicotinic receptor ligands discovered will be useful as pharmacological probes for better understanding the role of alpha3beta4 nicotinic receptors in nicotine addiction and reward, and can be developed as potential smoking cessation medications.