Development of GABABeta Receptor Compounds for Nicotine Dependence

描述(由申请人提供)：这是为响应计划公告PAR-08-238(NCDDDG)而提出的竞争性续期申请1 U01 MH69062。该项目目前的主要目标是合成用于治疗尼古丁依赖的新型γ-氨基丁酸(GABA)B受体正性调节剂，并对其进行体外和体内表征。拟议方案包括三个科学项目和一个行政核心(U19)(PD：A.Markou)。项目1(PI：M.G.Finn，加利福尼亚州拉霍亚的斯克里普斯研究所)将使用组合化学和点击化学设计、合成和提炼新的GABAB受体正调节剂。项目2(PI：P.Griffin，位于佛罗里达州朱庇特的斯克里普斯研究所)将使用基于细胞的功能性G蛋白偶联受体(GPCR)分析GABAB受体，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，加州大学圣地亚哥分校，加利福尼亚州拉霍亚)中进行尼古丁依赖大鼠模型的测试。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过程中的奖赏增强效应、线索诱导的尼古丁寻求恢复以及尼古丁戒断时的焦虑样行为。在之前资助期间的大量工作导致了第一批高选择性的GABAB受体正向调节剂，在尼古丁依赖的大鼠模型中具有预期的行为效应。因此，GABAB受体正向调制在治疗尼古丁依赖和潜在的对其他滥用药物的依赖方面的独特和新颖的策略已经建立了强有力的临床前概念验证。通过这一应用，我们寻求资金，通过以下方式巩固我们以前的成果：(A)扩大类药物活性物质的管道；(B)了解促进GABAB受体选择性正向调制的因素；以及(C)评估新合成的化合物如何影响尼古丁依赖大鼠模型的行为。这一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疗法。

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.