Orexin-1 Receptor Ligands for Drug Addiction

新出现的证据表明，食欲素系统是奖励和激励的关键调节因素。一直以来 证明食欲素，特别是食欲素-1受体参与药物自我给药， 药物依赖者戒毒过程中与药物相关的线索加工、奖赏和应激反应 动物。与行为学研究相比，OX1选择性配体的研究进展不大。配基 到目前为止，食欲素系统的发展主要集中在选择性OX2拮抗剂和/或双重OX1/OX2上 治疗失眠等睡眠障碍的拮抗剂。相反，只有少量的OX1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OX1特异通路的生理作用。尽管有很高的选择性，但Sb- 334867具有不良的生物利用度(10%)和稳定性，高剂量的Sb-334867(30 mg/kg)已被 显示会导致不想要的副作用(异常姿势和静止)，从而混淆对 行为实验。此外，小分子增食欲素激动剂尚未见报道，这些多肽 食欲素-A和B仍然是仅有的用于研究目的的OX1激动剂。食欲素-A和B相对 低效的食欲素受体(H 50 Nm)，要么是非选择性的，要么是轻微的OX2选择性。此外, 多肽对蛋白质分解很敏感，不会穿透血脑屏障，因此通常 直接进入中枢神经系统。总而言之，对选择性OX1激动剂和 拮抗剂将作为工具，进一步促进对OX1R药理学和关键的 食欲素在药物滥用和成瘾中扮演的角色。在这一应用中，我们计划开发OX1激动剂和 具有改进的效力、选择性和药代动力学特性的拮抗剂使用的策略包括 合理的化学合成，虚拟的屏幕和模拟多肽的开发。

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.