Nicotinic Ligands for Smoking Cessation

用于戒烟的烟碱配体

• 批准号: 8311764
• 负责人: Henry A. Lester
• 金额: $ 77.25万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311764
• 关键词: Agonist; American; Area; Behavior; Biology; Brain; Dependence; Development; Exhibits; Goals; Homo; Knowledge; Lead; Ligands; Long-Term Effects; Neurosciences; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pharmaceutical Preparations; Publications; Publishing; Receptor Activation; Research; Role; Series; Smoking; Testing; Therapeutic; Tobacco smoking; Up-Regulation; chronic Pb exposure; desensitization; drug development; drug discovery; ligand gated channel; mouse model; public health relevance; research study; smoking cessation; varenicline

DESCRIPTION (provided by applicant): The Caltech-Boulder-Targacept National Cooperative Drug Discovery and Development Group (NCDDDG) continues to be motivated by the hypothesis that successful smoking cessation compounds can selectively target just one or a few nicotinic acetylcholine receptor (nAChR) combinations. Nicotine addiction begins with the activation of these receptors, which are ligand-gated channels. Progress in this NCDDG and around the world during the 2005-2010 Project Period provided additional knowledge about the range of homo- and hetero-pentameric subtypes that do exist in the brain; about their localization; and about their specific roles in the constellation of phenomena that comprise nicotine addiction (tolerance, dependence, sensitization, and goal-seeking behavior). Nonetheless, knowledge remains partial, especially about the long-term effects of both nicotine and smoking cessation drugs. The 2010-2015 Project Period provides an iterative series of experiments to test hypotheses in these areas. (1) The NCDDDG will use accumulating knowledge to optimize lead compounds for smoking cessation. We will devote the first 2 yr of the Project Period to three lead compounds that emphasize a6-oriented and/or a4-oriented activity: varenicline, TCD-1010, and one other compound to be chosen by the Executive Committee. The compounds are expected to exhibit varying ratios of a6* to a4* activity. All these compounds will be at least partial agonists. We expect that all compounds will also desensitize a4* nAChRs; a6* desensitization will be studied in detail in Project 3. (2) It is also likely that successful smoking cessation compounds will themselves produce long-term changes in these target nAChRs. Therefore Projects 2 and 3 will use mouse models to explore possible upregulation, an adaptive change in nAChRs caused by chronic exposure to lead compounds. (3) The iterative experiments will, in turn, lead to synthesis of new compounds at Targacept (Project 1), and further testing during the final three yr of the 2010-2015 Project Period. This scientific approach will enable the Group, as well as other groups throughout the world, to optimize and develop lead compounds for smoking cessation. (4) While pursuing these goals in parallel, we intend to continue publishing all of our studies according to the usual standards that have characterized research in academic neuroscience.

描述（由申请人提供）：Caltech-Boulder-Targacept国家合作药物发现与开发小组（NCDDDG）的动机仍然是由于成功的吸烟戒烟化合物可以选择性地靶向一种或几种烟碱乙酰胆碱受体（NACHR）的合并。尼古丁成瘾始于这些受体的激活，即配体门控通道。在2005 - 2010年项目期间，在这个NCDDG和世界各地的进展提供了有关大脑中确实存在的同型和异源五聚体亚型范围的更多知识；关于他们的本地化；以及它们在构成尼古丁成瘾的现象星座中的特定作用（宽容，依赖性，敏感性和寻求目标行为）。尽管如此，知识仍然是部分的，特别是关于尼古丁和戒烟药物的长期影响。 2010-2015项目期间提供了一系列迭代的实验，以在这些领域测试假设。 （1）NCDDDG将使用积累的知识来优化戒烟的铅化合物。我们将将项目期的前两年投入到三种铅化合物，这些铅化合物强调了面向A6的和/或面向A4的活动：Varenicline，TCD-1010，以及执行委员会选择的另一种化合物。这些化合物有望表现为A6*与A4*活性的变化比例。所有这些化合物至少是部分激动剂。我们希望所有化合物也会脱敏A4* NACHRS； A6*脱敏将在项目3中进行详细研究。（2）成功的吸烟戒烟化合物本身可能会在这些目标NACHR中产生长期变化。因此，项目2和3将使用鼠标模型探索可能的上调，这是由于长期暴露于铅化合物而引起的NACHR的自适应变化。 （3）迭代实验反过来又将导致Targacept（项目1）的新化合物合成，并在2010-2015项目期间的最后三年内进行进一步测试。这种科学的方法将使该小组以及全世界的其他群体能够优化和开发戒烟的铅化合物。 （4）在同时追求这些目标的同时，我们打算按照在学术神经科学领域进行研究的通常标准继续发布所有研究。