Development of GABABeta Receptor Compounds for Nicotine Dependence

描述（由申请人提供）：根据项目公告PAR-08-238 (NCDDDG)，这是1 U01 MH69062拨款的竞争性续期申请。本项目的主要目标是合成新型氨基丁酸（GABA） B受体阳性调节剂，并在体外和体内鉴定其用于治疗尼古丁依赖。该计划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， Scripps研究所，La Jolla, California）将使用组合化学和点击化学设计、合成和改进新的GABAB受体正调剂。项目2 （PI: P. Griffin, The Scripps Research Institute, Jupiter, Florida）将利用基于细胞的功能性g蛋白偶联受体（GPCR）检测GABAB受体，分析候选GABAB受体阳性调节剂的体外药理学。项目2还将评估所选化合物的体外代谢、体内脑渗透和药代动力学特性。具有所需性质组合的化合物将在项目3 （PI: A. Markou，加州大学圣地亚哥分校，La Jolla, California）中在尼古丁依赖的大鼠模型中进行测试。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励增强作用，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GABAB受体的第一个高选择性阳性调节剂在尼古丁依赖大鼠模型中具有预期的行为效应。因此，GABAB受体阳性调节的独特和新颖策略在治疗尼古丁依赖以及潜在的滥用其他药物依赖方面已经建立了强有力的临床前概念证明。有了这一申请，我们寻求资金，以建立我们以前的成果：(a)扩大药物样活性剂的管道；(b)了解促进GABAB受体选择性正调节的因素；(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。这个多学科研究项目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。

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.