Development of Orexin-1 Receptor Antagonists for Drug Addiction

用于治疗毒瘾的 Orexin-1 受体拮抗剂的开发

基本信息

批准号：
8465862
负责人：
Theodore M Kamenecka
金额：
$ 162.47万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465862
关键词：
Accounting Animal Model Behavior Behavioral Biological Assay Brain Calcium Cell Line Cells Cessation of life Circadian Rhythms Clinical Clinical assessments Cues Cyclic AMP Data Development Disease Drug Addiction Drug Kinetics Drug Targeting Drug toxicity Family Florida Fluorescence G alpha q Protein Goals Health Human Hypothalamic structure In Vitro Inositol Phosphates Interdisciplinary Study Intravenous Knockout Mice Laboratories Lateral Malignant neoplasm of lung Mediating Metabolic Monitor Mus Neurons Neuropeptides Nicotine Nicotine Dependence Pathway interactions Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Play Pre-Clinical Model Procedures Property Rattus Receptor Cell Relapse Research Rewards Role Self Administration Self Stimulation Series Signal Transduction Site Smoker Smoking Stress Structure-Activity Relationship Substance abuse problem System Testing Therapeutic Agents Time Tobacco Tobacco Dependence Tobacco smoke Tobacco smoking Toxic effect Wild Type Mouse addiction base behavior test disorder later incidence prevention drug addict drug discovery drug metabolism heuristics hypocretin in vivo novel novel therapeutics null mutation orexin 1 receptor orexin A orexin B orexin B receptor receptor receptor coupling receptor function receptor internalization response screening smoking cessation tool transmission process

项目摘要

DESCRIPTION (provided by applicant): This application describes a highly integrated series of projects aiming to develop orexin-1 (OX1) receptor antagonists for treatment of tobacco dependence. Project 1 will utilize iterative medicinal chemistry based on structure-activity relationships (SAR) to discover new classes of potent and selective OX1 receptor antagonists. SAR will be used to optimize new classes of OX1 receptor antagonists for drug metabolism and pharmacokinetics (DMPK), and brain penetration properties. We have already generated excellent OX1 receptor antagonists as starting points for SAR based on our ongoing medicinal chemistry efforts. Project 2 will support SAR by testing new compounds in in vitro cell-based functional assays for OX1 receptors (and appropriate counter-screens) to determine potency and selectivity. We have already established and validated a range of OX1 receptor cell-based assays, and have successfully used these assays to identify starting points for SAR. Project 3 will test new classes of potent and selective OX1 receptor antagonists to identify those with the most favorable physiochemical and brain penetration profiles, and identify those least likely to have toxicity in humans. Project 4 will test the in vivo efficacy of novel OX1 receptor antagonists in cutting-edge behavioral procedures that assess addiction-related behavioral effects of nicotine. Importantly, have developed a new IV nicotine self-administration procedure for mice, and will assess novel OX1 receptor antagonists in wild type and OX1 receptor knockout mice to determine their behavioral selectivity. This integrated multidisciplinary research plan will capitalize on the unique drug discovery capabilities at Scripps Florida, and promises to yield novel therapeutic entities for the prevention of relapse in human tobacco smokers.

描述（由申请人提供）：本申请描述了一系列高度集成的项目，旨在开发Orexin-1（OX1）受体拮抗剂来治疗烟草依赖性。项目1将基于结构活性关系（SAR）利用迭代药物化学来发现新的有效OX1受体拮抗剂。 SAR将用于优化用于药物代谢和药代动力学（DMPK）的新型OX1受体拮抗剂和脑穿透性特性。根据我们正在进行的药物化学工作，我们已经产生了出色的OX1受体拮抗剂作为SAR的起点。项目2将通过在基于体外细胞的功能测定中测试OX1受体（和适当的反屏幕）中的新化合物来支持SAR，以确定效力和选择性。我们已经建立并验证了一系列OX1受体基于基于OX1的基于基于OX1受体的测定，并成功使用了这些测定方法来识别SAR的起点。项目3将测试新的有效OX1受体拮抗剂的新类别，以鉴定具有最有利的生理和脑穿透性曲线的人，并确定那些最不可能在人类中毒性的人。项目4将测试新型OX1受体拮抗剂的体内功效在评估尼古丁与成瘾相关的行为影响的尖端行为程序中。重要的是，已经为小鼠开发了一种新的IV尼古丁自我给药程序，并将评估野生型和OX1受体敲除小鼠的新型OX1受体拮抗剂，以确定其行为选择性。这项综合的多学科研究计划将利用佛罗里达州斯克里普斯（Scripps Florida）独特的药物发现能力，并有望产生新颖的治疗实体，以预防人类烟草吸烟者复发。