Development of Orexin-1 Receptor Antagonists for Drug Addiction

描述（由申请人提供）：本申请描述了旨在开发用于治疗烟草依赖的食欲素-1（OX 1）受体拮抗剂的一系列高度集成的项目。项目1将利用基于结构-活性关系（SAR）的迭代药物化学来发现新类别的强效和选择性OX 1受体拮抗剂。SAR将用于优化新型OX 1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OX 1受体拮抗剂作为SAR的起点。项目2将通过在OX 1受体（和适当的反筛选）的体外基于细胞的功能测定中测试新化合物来支持SAR，以确定效力和选择性。我们已经建立并验证了一系列基于OX 1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将测试新类别的有效和选择性的OX 1受体拮抗剂，以确定那些具有最有利的理化和脑渗透概况，并确定那些最不可能有毒性的人。项目4将测试新型OX 1受体拮抗剂的体内功效 在评估尼古丁成瘾相关行为影响的尖端行为程序中。重要的是，开发了一种新的小鼠IV尼古丁自我给药程序，并将在野生型和OX 1受体敲除小鼠中评估新型OX 1受体拮抗剂，以确定其行为选择性。这项综合性的多学科研究计划将利用斯克里普斯佛罗里达独特的药物发现能力，并有望产生新的治疗实体，用于预防人类吸烟者的复发。

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.