Development of Orexin-1 Receptor Antagonists for Drug Addiction

描述（由申请人提供）：本申请描述了一系列高度整合的项目，旨在开发用于治疗烟草依赖的食欲素-1 （OX1）受体拮抗剂。项目1将利用基于构效关系（SAR）的迭代药物化学来发现新的强效和选择性OX1受体拮抗剂。SAR将用于优化新型OX1受体拮抗剂的药物代谢和药代动力学（DMPK）以及脑渗透特性。基于我们正在进行的药物化学工作，我们已经产生了优秀的OX1受体拮抗剂作为SAR的起点。项目2将通过对OX1受体（和适当的反筛）的体外细胞功能分析测试新化合物来支持SAR，以确定其效力和选择性。我们已经建立并验证了一系列基于OX1受体细胞的检测方法，并成功地使用这些检测方法来确定SAR的起始点。项目3将测试新类别的强效和选择性OX1受体拮抗剂，以确定那些具有最有利的物理化学和脑渗透特征，并确定那些最不可能对人类产生毒性的拮抗剂。项目4将测试新型OX1受体拮抗剂的体内疗效

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.