Drug Discovery Group for Nicotine Dependence Treatment

在药物依赖障碍中，尼古丁依赖是传播最广泛的，对世界健康和经济有强烈影响。烟草流行是一个全球性问题；全世界15岁以上人口的三分之一，即11亿人吸烟。世界卫生组织估计，到2025年，全球每年将有1000万人死于与烟草有关的疾病。戒烟治疗性价比很高，药物治疗是 普遍推荐用于无特定禁忌症的尼古丁依赖的治疗。然而，大多数吸烟者即使接受治疗也不会戒烟。目前可用的治疗方法没有利用成瘾和奖赏的神经生物机制方面的最新进展，这些知识使合理设计的治疗方法的开发成为可能，特别是针对参与尼古丁奖赏回路的系统。现有的和 新的药物疗法和预防努力是提高戒烟率和减少与烟草使用有关的过早和可预防的发病率和死亡率的关键。 这种RFA促使三个组织对尼古丁依赖的药物治疗长期感兴趣， 马萨诸塞州总医院(MGH)、麦克莱恩医院脑成像中心(BIC)和葛兰素史克(GSK)联手成立了NCDDG-MD/NA集团。该小组的主要目标是识别和测试在尼古丁奖赏和渴望中影响关键神经系统的有希望的化合物。在这个药物发现的协作小组项目中，我们将结合筛选多种潜在的先导化合物，以及临床前和 两种化合物的临床测试和活体脑成像措施。具体地说，我们将1)在神经化学、电生理学、行为和动物大脑成像分析中筛选多种先导化合物，2)在人类新型72小时尼古丁渴求范式中筛选临床前工作中确定的多种有希望的化合物，3)进行临床试验，以测试与安慰剂和安非他酮相比，最有希望的两种化合物的戒烟效果，以及4)使用体内神经成像来确定人类治疗反应和复发的替代标记物。这一努力将促进我们对尼古丁依赖、早期戒断/治疗反应和复发所涉及的机制的理解，将促进我们对哪种类型的药物在治疗尼古丁依赖方面有效的理解，将测试一系列假定的替代标记物的临床反应，旨在加速评估有效药物对尼古丁依赖的有效性的过程。 在动力充足的试验中，有两种化合物可以治疗尼古丁依赖。我们将调查的化合物将来自葛兰素史克正在开发的针对尼古丁依赖的大型现有化合物组合。每个组织都将为项目的实施和成功作出独特的人员和资源贡献。

Among drug dependence disorders, nicotine dependence is the most widely diffused, with a strong impact on the world's health and economy. The tobacco epidemic is a global problem; one-third of the worldwide population over 15 years of age or 1.1 billion people smoke. By the year 2025, the WHO estimates there will be 10 million tobaccorelated deaths per year worldwide. Smoking cessation treatment is highly cost-effective, and pharmacotherapy is universally recommended for treatment of nicotine dependence in the absence of specific contraindications. However, the majority of smokers do not quit even with treatment. Currently available treatments do not exploit recent advances inknowledge of neurobiologic mechanisms of addiction and reward that have made possible the development of rationally designed treatments targeting specifically those systems involved in nicotine reward circuitry. Existing and new pharmacotherapies along with prevention efforts are key to improving smoking cessation rates and reducing the premature and preventable morbidity and mortality associated with tobacco use. This RFA has prompted three organizations with longstanding interest in pharmacotherapy for nicotine dependence, Massachusetts General Hospital (MGH), McLean Hospital Brain Imaging Center (BIC), and GlaxoSmithKline (GSK), to join forces for the proposed NCDDG-MD/NA Group. The primary objective of this group is to identify and test promising compounds that affect critical neural systems in nicotine reward and craving. In this collaborative group project for drug discovery, we will combine screening of multiple potential lead compounds, with pre-clinical and clinical testing of two compounds and in vivo brain imaging measures. Specifically, we will 1) screen multiple lead compounds in neurochemistry, electrophysiology, behavioral and animal brain imaging assays, 2) screen multiple promising compounds identified in the preclinical work in a novel human 72 hour nicotine craving paradigm, 3) perform clinical trials to test the efficacy of the most promising two compounds for smoking cessation, compared with placebo and bupropion and 4) use in vivo neuroimaging to identify surrogate markers for treatment response and relapse in humans. This effort will advance our understanding of mechanisms involved in nicotine dependence, early abstinence/treatment response and relapse, will advance our understanding of what types of agents are effective in treating nicotine dependence, will test a battery of putative surrogate markers for clinical response aimed at accelerating the process by which effective drugs can be assessed for efficacy in nicotine dependence and will test two compounds for nicotine dependence in adequately powered trials. The compounds that we will investigate will be drawn from the large, existing portfolio of compounds under development for nicotine dependence at GSK. Each organization will make a unique contribution of personnel and resources to the implementation and success of the project.