Development of Orexin-1 Receptor Antagonists to Prevent Drug Relapse

开发 Orexin-1 受体拮抗剂以预防药物复发

基本信息

批准号：
7496983
负责人：
Paul J. Kenny
金额：
$ 42.41万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7496983
关键词：
Abstinence Adverse effects Agonist Animal Model Behavior Biological Assay Brain Calcium Calcium Signaling Cell Line Cells Chinese Hamster Chinese Hamster Ovary Cell Cholecystokinin Circadian Rhythms Class Cocaine Cocaine Dependence Cocaine Users Commit Corticotropin-Releasing Hormone Coupled Depth Detection Development Disease Drug Addiction Drug Kinetics Dyes Family Florida G alpha q Protein GTP-Binding Proteins Goals Half-Life Housing Human Hypothalamic structure Image In Vitro Interdisciplinary Study Knowledge Laboratories Lateral Ligand Binding Measurement Measures Membrane Potentials Metabolic Modeling Neuropeptides Nucleus Accumbens Ovary Pathway interactions Penetration Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Play Pre-Clinical Model Prefrontal Cortex Procedures Process Property Rate Rattus Reader Relapse Research Research Personnel Rewards Role Scientist Screening procedure Self Stimulation Serotonin Signal Transduction Stress Structure-Activity Relationship Substance abuse problem Testing Triage Ventral Tegmental Area Vesicular stomatitis Indiana virus Work addiction base design disorder later incidence prevention drug addict drug discovery drug metabolism drug relapse heuristics hypocretin in vivo neuropeptide Y novel novel therapeutics orexin 1 receptor orexin A orexin B orexin B receptor prevent programs receptor receptor coupling receptor internalization response

项目摘要

DESCRIPTION (provided by applicant): This application is in response to RFA-DA-07-006 to design, synthesize and test in relevant preclinical models, potential treatments for drug addiction. The pharmacological approach proposed is to develop new classes of potent and selective orexin-1 (OX1) receptor antagonists that may prove efficacious in preventing relapse in abstinent human cocaine addicts. To accomplish this aim, we have assembled a team of highly motivated researchers with expertise in every aspect of the drug discovery process and in animal models of addiction. Specific Aim I will involve establishing a robust in vitro cell-based functional assays for OX1 receptors (and appropriate counter-screens) which can support a medicinal chemistry program aimed at developing new classes of potent and selective OX1 receptor antagonists. Specifically, we will examine changes in agonist-induced increases of intracellular calcium signaling via membrane potential dyes and a fluorescent plate reader (FLIPR) in CHO cells stably expressing human OX1 receptors (OX1 receptors couple to Gq).In addition, we will establish a novel agonist-induced, G-protein-independent, receptor internalization assay coupled with high content imaging to make quantitative measurements of 0X1 receptor internalization upon agonist stimulation in U20S cells stably expressing OX1 receptors. This internalization assay will provide a counter-screen to the calcium signaling assays. Specific Aim II will utilize an iterative medicinal chemistry program based on structure-activity relationships (SAR) to discover new classes of potent and selective OX1 receptor antagonists. Structure-activity relationships will be employed to optimize new classes of OX1 receptor antagonists for drug metabolism and pharmacokinetics (DMPK), and brain penetration properties. Specific Aim III will test new classes of potent and selective OX1 receptor antagonists with favorable DMPK and brain penetration in the rat stress-induced reinstatement model of relapse to cocaine seeking. In addition, the intrinsic rewarding properties of OX1 receptor antagonists that block relapse-like behavior will be assessed in the intracranial self-stimulation (ICSS) thresholds procedure in rats in order to triage compounds with potential abuse liability. Such an 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 addicts.

描述（由申请人提供）：此申请响应RFA-DA-07-006来设计，合成和测试相关的临床前模型，潜在的药物成瘾治疗方法。提出的药理学方法是开发新的有效和选择性的Orexin-1（OX1）受体拮抗剂，这些拮抗剂可能会有效防止戒除的人类可卡因成瘾者复发。为了实现这一目标，我们在药物发现过程的各个方面和成瘾的动物模型中组建了一个具有专业知识的高度积极进取的研究人员。具体目的I将涉及建立用于OX1受体（和适当的反屏幕）的强大基于细胞的功能测定，该测定可以支持旨在开发新的有效和选择性OX1受体拮抗剂的药物化学计划。具体而言，我们将检查激动剂诱导的细胞内钙信号的增加通过膜电位染料和稳定表达人OX1受体的CHO细胞中的荧光板读取器（FLIPR）（FLIPR）（OX1受体夫妇与GQ）。新型激动剂诱导的，与G蛋白非依赖性的受体内在化测定法以及高含量成像相结合，在U20S细胞中稳定表达OX1受体的U20S细胞中的激动剂刺激对0x1受体内在化进行定量测量。该内部化测定将为钙信号测定提供一个反屏幕。具体目标II将基于结构活性关系（SAR）利用迭代药物化学计划，以发现新的有效OX1受体拮抗剂类别。结构活性关系将用于优化用于药物代谢和药代动力学（DMPK）和脑渗透特性的新的OX1受体拮抗剂。特定的目标III将测试具有良好DMPK和大脑渗透的新型有效OX1受体拮抗剂在大鼠应力引起的恢复模型的复发模型中，以期寻求可卡因。此外，将在大鼠的颅内自我刺激（ICS）阈值程序中评估OX1受体拮抗剂的固有奖励性能，以评估具有潜在虐待责任的分类化合物。这样的综合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，以预防人类成瘾者复发。