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: 8282981
• 负责人: ATHINA MARKOU
• 金额: $ 147.34万
• 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/8282981
• 关键词: Affect; Aminobutyric Acids; Animal Model; Anxiety; Applications Grants; Behavior; Behavioral; Biological Assay; Brain; California; Cells; Chemistry; Cues; Dependence; Development; Drug Kinetics; Florida; Funding; G-Protein-Coupled Receptors; GABA-B Receptor; Human; In Vitro; Individual; Interdisciplinary Study; Jupiter; Metabolism; Modeling; NIH Program Announcements; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Penetration; Pharmaceutical Preparations; Pharmacology; Procedures; Property; Rattus; Research Institute; Rewards; Scientist; Selection Criteria; Self Administration; Self Stimulation; Testing; Therapeutic; Tobacco smoking; Work; base; combinatorial; design; drug metabolism; drug of abuse; in vivo; in vivo Model; innovation; novel; novel strategies; pharmacokinetic characteristic; pre-clinical; programs; public health relevance; receptor; response

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）：这是对计划公告PAR-08-238（NCDDDG）的竞争续订授予1 U01 MH69062。现在，该项目的主要目标集中于合成，体外和体内表征的新型Y-氨基丁酸（GABA）B受体阳性调节剂用于治疗烟碱依赖性。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（PI：M.G. Finn，Scripps Research Institute，La Jolla，加利福尼亚州）将使用组合和点击化学设计，合成和完善新的GABAB受体正阳性调节器。项目2（PI：P. Griffin，Scripps研究所，佛罗里达州木星），将使用基于细胞的功能性G蛋白偶联受体（GPCR）测定法的候选GABAB受体正阳性调节剂的体外药理学来介绍GABAB受体。项目2还将评估所选化合物的体外代谢以及体内脑渗透和药代动力学特征。将在项目3（PI：A. Markou，加利福尼亚州加利福尼亚州加利福尼亚州的加利福尼亚大学，加利福尼亚州拉霍亚大学）中测试具有所需属性组合的化合物。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励增强作用，在尼古丁戒断期间，提示诱导的尼古丁寻求尼古丁寻求的行为以及类似焦虑的行为。在先前资助的时期，广泛的工作导致了GABAB受体的第一个高度选择性的阳性调节剂，并在尼古丁依赖性大鼠模型中具有所需的行为效应。因此，已经为GABAB受体阳性调节的独特而新颖的策略建立了强大的临床前概念证明，并可能依赖于其他滥用药物。通过此应用，我们寻求资金以以下方式建立以下结果：（a）扩大类似毒品的活性剂的管道； （b）理解促进GABAB受体选择性阳性调节的因素； （c）评估新合成的化合物如何影响尼古丁依赖性大鼠模型中的行为。这项多学科研究计划将参与科学家的互补专业知识融为一体，以为人类的尼古丁依赖提供创新的潜在疗法。