Orexin-1 Receptor Ligands for Drug Addiction

描述（由申请人提供）：越来越多的证据表明，食欲素系统是奖励和动机的关键调节器。研究表明，食欲素，尤其是食欲素-1受体，在药物依赖动物戒断期间参与药物自我给药、药物相关线索加工、奖励和应激反应。与行为学研究相比，OX1选择性配体的研究尚未取得进展。到目前为止，食欲素系统的配体开发主要集中在选择性OX2拮抗剂和/或双重OX1/OX2拮抗剂上，用于治疗失眠等睡眠障碍。相反，只有少数OX1选择性拮抗剂被描述，SB-334867是唯一用于评估体内OX1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，但它具有不理想的生物利用度（10%）和稳定性，高剂量SB-334867 （30mg/kg）已被证明会导致不良副作用（异常姿势和不动），这使行为实验的解释混淆。此外，小分子食欲素激动剂尚未报道，肽食欲素a和B仍然是唯一可用的OX1激动剂用于研究目的。orexin - a和B在orexin受体上的效价相对较低（~ 50nM），要么是非选择性的，要么是轻微的OX2选择性。此外，多肽易受蛋白水解，不穿透血脑屏障，因此通常直接给药到中枢神经系统。综上所述，对选择性OX1激动剂和拮抗剂的需求尚未得到满足，这将有助于进一步了解OX1R药理学以及食欲素在药物滥用和成瘾中的关键作用。在这项应用中，我们计划利用合理的化学合成、虚拟筛选和拟肽开发等策略，开发具有更高效力、选择性和药代动力学特性的OX1激动剂和拮抗剂。

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. PUBLIC HEALTH RELEVANCE: Emerging evidence suggests that orexin 1 receptors play a critical role in a variety of physiological processes including reward and motivation and therefore, represent a valuable target in medication development for the treatment of drug abuse and addiction. This project plans to develop potent and selective agonists and antagonists for this receptor. These ligands will serve as tools to probe the signaling mechanisms and in vivo function of this receptor and could expedite the ultimate development of novel therapies for the treatment of conditions mediated by orexin signaling including drug abuse and addiction.