Subtype-Selective Nicotinic Receptor Ligands as Smoking Cessation Pharmacotherapy

说明（由申请人提供）：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。仅在美国，每年就有44万人死于吸烟引起的疾病，长期吸烟者中有一半将死于与吸烟有关的疾病。吸烟有很强的依赖性——70%的吸烟者说他们想戒烟，但90%以上的人都失败了。对大多数吸烟者来说，烟草使用是由尼古丁依赖维持的。目前用于戒烟的药物治疗是非选择性的，效果也很低。因此，该申请的长期目标是开发额外的、改进的药物疗法。为此，我们将首先验证以下假设：尼古丁乙酰胆碱受体的alpha3beta4亚型是尼古丁药物开发的合适靶点，受体拮抗剂可以减少尼古丁和其他滥用药物的有益方面。虽然alpha3beta4拮抗剂已显示出减少尼古丁和其他药物滥用的自我给药的功效，但目前还没有选择性拮抗剂对该位点起作用。选择性和高亲和力的配体将在分子模型研究和受体选择性药效团开发的基础上设计。激动剂和拮抗剂活性的分子决定因素也将被探讨。化合物将在体外测试与转染了alpha3beta4和alpha4beta2烟碱乙酰胆碱受体亚型的HEK细胞系的结合亲和力和功能活性。将使用膜片钳电生理技术更仔细地检查铅化合物，以确定活性是否依赖于电压或活性，并确定受体的脱敏率。最后，将对铅化合物进行测试，以确定它们是否会减弱小鼠对尼古丁的自我摄入。由于alpha3beta4拮抗剂被认为可以阻断许多药物滥用引起的奖赏，因此还将对铅化合物进行测试，以确定它们是否会减弱吗啡和可卡因引起的小鼠的位置偏好。

DESCRIPTION (provided by applicant): 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 determine 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.