Development of GABABeta Receptor Compounds for Nicotine Dependence

开发治疗尼古丁依赖的 GABAβ 受体化合物

• 批准号: 8153872
• 负责人: ATHINA MARKOU
• 金额: $ 149.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8153872
• 关键词: Development; GABABeta; Receptor; Compounds; Nicotine

DESCRIPTION (provided by applicant): This is competing renewal application of grant 1 U01 MH69062 in response to Program Announcement PAR-08-238 (NCDDDG). The main objectives of this project are now focused on the synthesis, and in vitro and in vivo characterization of novel y-aminobutyric acid (GABA) B receptor positive modulators for the treatment of nicotine dependence. The proposed program consists of three Scientific Projects and an Administrative Core (U19) (PD: A. Markou). Project 1 (PI: M.G. Finn, The Scripps Research Institute, La Jolla, California) will design, synthesize, and refine new GABAB receptor positive modulators, using both combinatorial and click chemistry. Project 2 (PI: P. Griffin, The Scripps Research Institute, Jupiter, Florida), will profile the in vitro pharmacology of candidate GABAB receptor positive modulators using cell-based functional G-protein coupled receptor (GPCR) assays for GABAB receptors. Project 2 will also assess the in vitro metabolism, and in vivo brain penetration and pharmacokinetic characteristics of selected compounds. Compounds with the desired combination of properties will be tested in Project 3 (PI: A. Markou, Univ of California San Diego, La Jolla, California) in well validated rat models of nicotine dependence. These in vivo models will include nicotine self-administration, reward-enhancing effects of nicotine in the intracranial self-stimulation procedure, cue-induced reinstatement of nicotine-seeking and anxiety-like behavior during nicotine withdrawal. Extensive work during the previously funded period resulted in the first highly selective positive modulators for GABAB receptors with the desired behavioral effects in rat models of nicotine dependence. Thus, strong preclinical proof-of-concept has been established for the unique and novel strategy of GABAB receptor positive modulation in the treatment of nicotine dependence, and potentially dependence on other drugs of abuse. With this application, we seek funding to build on our previous results by: (a) expanding the pipeline of drug-like active agents; (b) understanding the factors that promote selective positive modulation of GABAB receptors; and (c) assessing how the newly synthesized compounds affect behaviors in rat models of nicotine dependence. This multidisciplinary research program integrates the complementary expertise of the participating scientists to provide innovative potential therapeutics for nicotine dependence in humans.

描述（由申请人提供）：这是响应计划公告PAR-08-238（NCDDDG）的资助1 U 01 MH 69062的竞争性续期申请。本项目的主要目标是合成新型γ-氨基丁酸（GABA）B受体阳性调节剂，并在体外和体内进行表征，用于治疗尼古丁依赖。拟议的计划包括三个科学项目和一个行政核心（U19）（PD：A。Markou）。项目1（主要负责人：M.G. Finn，斯克里普斯研究所，拉霍亚，加州）将设计，合成和完善新的GABAB受体阳性调节剂，使用组合和点击化学。项目2（PI：P. Griffin，The Scripps Research Institute，Jupiter，佛罗里达）将使用基于细胞的GABAB受体功能性G蛋白偶联受体（GPCR）测定来描述候选GABAB受体阳性调节剂的体外药理学。项目2还将评估选定化合物的体外代谢、体内脑渗透和药代动力学特征。具有所需性能组合的化合物将在项目3（PI：A. Markou，Univ of加州圣地亚哥，拉霍亚，加州）。这些体内模型将包括尼古丁自我给药、尼古丁在颅内自我刺激程序中的奖赏增强效应、尼古丁戒断期间尼古丁寻求和焦虑样行为的线索诱导恢复。在先前资助期间的大量工作导致了第一个高选择性的GABAB受体阳性调节剂，在尼古丁依赖的大鼠模型中具有所需的行为效果。因此，已经为治疗尼古丁依赖和对其他滥用药物的潜在依赖的独特且新颖的GABAB受体正调节策略建立了强有力的临床前概念验证。有了这个应用程序，我们寻求资金，以建立在我们以前的结果：（a）扩大管道的药物样活性剂;（B）了解的因素，促进GABAB受体的选择性积极调节;和（c）评估新合成的化合物如何影响行为的尼古丁依赖大鼠模型。这项多学科研究计划整合了参与科学家的互补专业知识，为人类尼古丁依赖提供创新的潜在治疗方法。