Orexin-1 Receptor Ligands for Drug Addiction

Orexin-1 受体配体治疗毒瘾

• 批准号: 8415521
• 负责人: Yanan Zhang
• 金额: $ 25.41万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415521
• 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

DESCRIPTION (provided by applicant): 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 (~ 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.

描述（由申请人提供）：新出现的证据表明增食欲素系统是奖励和激励的关键调节器。已经证明，食欲素，特别是食欲素-1受体，参与药物依赖动物在药物戒断期间的药物自我给药、药物相关线索处理、奖励和应激反应。与行为研究相反，OX 1选择性配体的开发尚未取得进展。迄今为止，食欲素系统的配体开发主要集中在针对失眠等睡眠障碍的选择性OX 2拮抗剂和/或双重OX 1/OX 2拮抗剂上。相反，仅描述了少量的OX 1选择性拮抗剂，SB-334867代表了唯一用于评价体内OX 1特异性途径生理作用的药理学工具。尽管SB- 334867具有高选择性，但其生物利用度（10%）和稳定性不理想，高剂量SB-334867（30 mg/kg）已被证明会导致不必要的副作用（异常姿势和不动），混淆行为实验的解释。此外，还没有报道小分子食欲素激动剂，并且肽食欲素-A和B仍然是用于研究目的的唯一可用的OX 1激动剂。食欲素-A和B对食欲素受体具有相对低的效力（~ 50 nM），并且是非选择性的或轻微的OX 2选择性的。此外，肽对蛋白水解敏感，不穿透血脑屏障，因此通常直接施用到CNS中。总之，对选择性OX 1激动剂和拮抗剂存在未满足的需求，这些激动剂和拮抗剂将用作进一步促进理解OX 1 R药理学和食欲素在药物滥用和成瘾中发挥的关键作用的工具。在本申请中，我们计划开发具有改进的效力、选择性和药代动力学特性的OX 1激动剂和拮抗剂，使用包括合理化学合成、虚拟筛选和拟肽开发的策略。