Orexin-1 Receptor Ligands for Drug Addiction

新出现的证据表明，食欲素系统是奖励和动机的关键调节器。已经 表明食欲素，特别是食欲素-1受体，参与药物自我给药， 药物依赖者戒毒期间药物相关线索加工、奖赏和应激反应 动物与行为研究相反，OX 1选择性配体的开发尚未取得进展。配体 迄今为止，食欲素系统的开发集中在选择性OX 2拮抗剂和/或双重OX 1/OX 2 用于睡眠障碍如失眠症的拮抗剂。相反，只有少量的OX 1选择性 已经描述了拮抗剂，SB-334867代表了唯一的药理工具， 用于评估体内OX 1特异性途径的生理作用。尽管选择性高，SB- 334867具有不良的生物利用度（10%）和稳定性，高剂量SB-334867（30 mg/kg）已被 显示会导致不必要的副作用（异常姿势和不动）， 行为实验此外，还没有报道小分子食欲素激动剂， 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具有相对 对食欲素受体的效力低（H 50 nM），并且是非选择性的或轻微的OX 2选择性。此外，本发明还提供了一种方法， 肽对蛋白水解敏感，不穿透血脑屏障，因此通常 直接给药至CNS。总之，对选择性OX 1激动剂和 拮抗剂，将作为工具，以进一步促进理解OX 1 R药理学和关键的 食欲素在药物滥用和成瘾中的作用。在本申请中，我们计划开发OX 1激动剂， 具有改进的效力、选择性和药代动力学性质的拮抗剂， 合理的化学合成、虚拟筛选和拟肽开发。

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.