Orexin-1 Receptor Ligands for Drug Addiction

Orexin-1 受体配体治疗毒瘾

基本信息

批准号：
8791393
负责人：
Yanan Zhang
金额：
$ 49.99万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791393
关键词：
Adverse effects Agonist Amino Acid Substitution Amino Acids Animals Behavioral Biological Assay Biological Availability Blood - brain barrier anatomy Brain Calcium Computer Simulation Cues Development Dose Drug Addiction Drug Kinetics Drug abuse Goals Lead Libraries Ligands Mediating Modeling Molecular Conformation Motivation Pathway interactions Pattern Penetration Peptide Fragments Peptide Library Peptides Peptoids Pharmaceutical Preparations Pharmacology Phase Physiological Physiological Processes Play Posture Principal Investigator Property Proteolysis Reporting Research Rewards Role SB-334867 Scanning Self Administration Shapes Signal Transduction Site-Directed Mutagenesis Sleep Disorders Sleeplessness Structure Structure-Activity Relationship System Testing Tetrahydroisoquinolines Translating Vertebral column Work analog base biological adaptation to stress chemical synthesis drug abstinence hypocretin improved in vivo novel orexin 1 receptor orexin A peptidomimetics pharmacophore programs receptor receptor binding receptor function research study response reward processing scaffold small molecule therapy development tool virtual

项目摘要

Emerging evidence indicates the orexin system is a key regulator for reward and motivation. It has been demonstrated that orexins, and the orexin-1 receptor in particular, are involved in drug self-administration, drug-associated cue processing, reward, and stress responses during drug abstinence in drug-dependent animals. In contrast to behavioral studies development of OX1 selective ligands has not progressed. Ligand development for the orexin system thus far focused on selective OX2 antagonists and/or dual OX1/OX2 antagonists for sleep disorders such as insomnia. Conversely, only a small number of OX1 selective antagonists have been described and SB-334867 represents the only pharmacological tool that has been employed in evaluating the physiological role of OX1 specific pathways in vivo. Despite its high selectivity, SB- 334867 has undesirable bioavailability (10%) and stability, and high doses of SB-334867 (30mg/kg) have been shown to lead to unwanted side effects (abnormal posture and immobility) that confound interpretation of behavioral experiments. Moreover, small molecule orexin agonists have not been reported and the peptides orexin-A and B remain the only available OX1 agonists for research purposes. Orexin-A and B have relatively low potency at the orexin receptors (H 50nM) and are either non-selective or slightly OX2 selective. In addition, peptides are susceptible to proteolysis, do not penetrate the blood brain barrier and therefore, are normally directly administrated into the CNS. Taken together, there is an unmet need for selective OX1 agonists and antagonists that will serve as tools to further facilitate understanding of OX1R pharmacology and the critical role orexins play in drug abuse and addiction. In this application, we plan to develop OX1 agonists and antagonists with improved potency, selectivity and pharmacokinetic properties using strategies including rational chemical synthesis, virtual screens and peptidomimetic development.

新兴证据表明，奥雷敦素系统是奖励和动机的关键调节剂。它一直证明Orexins和Orexin-1受体尤其参与药物自我给药，药物依赖药物戒酒期间与药物相关的提示处理，奖励和压力反应动物。与行为研究的发展相反，OX1选择性配体的发展尚未进行。配体到目前为止，Orexin系统的开发集中在选择性OX2拮抗剂和/或双OX1/OX2上睡眠障碍的拮抗剂，例如失眠。相反，只有少数OX1选择性已经描述了拮抗剂，SB-334867代表了唯一的药理学工具用于评估体内OX1特定途径的生理作用。尽管具有很高的选择性，但SB- 334867具有不良的生物利用度（10％）和稳定性，高剂量的SB-334867（30mg/kg）是证明会导致不必要的副作用（异常姿势和固定性），使解释的解释行为实验。此外，尚未报道小分子或小分子或 Orexin-A和B仍然是用于研究目的的唯一可用的OX1激动剂。 Orexin-A和B相对在Orexin受体（H 50nm）处的低效力，是非选择性或略微OX2选择性的。此外，肽容易受到蛋白水解的影响，不要穿透血脑屏障，因此通常是直接管理到中枢神经系统。综上所述，选择性ox1激动剂的需求未满足将作为进一步理解OX1R药理学和关键的对抗者角色OREXIN在药物滥用和成瘾中起着作用。在此应用中，我们计划开发OX1激动剂和使用包括在内的策略（包括）合理的化学合成，虚拟筛选和肽型的发展。