DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

说明(申请人提供)：伤害性感受受体(NOP，以前称为阿片受体样受体ORL1)是阿片受体家族的第四个新成员。虽然NOP及其内源性配体伤害素或孤儿FQ的功能还不清楚，但这个受体系统在阿片类药物相关的抗伤害、耐受和奖赏中发挥着明显的调节作用。这些功能，加上受体在焦虑、学习记忆、摄食等方面的作用，表明新型小分子NOP配体在疼痛、药物成瘾等方面具有潜在的治疗应用前景。在我们目前的资助期间，我们发现了几个新的NOP配体，并建立了小分子配体的结合、选择性和内在活性的结构-活性关系(SAR)。我们的合成孔径雷达研究已经确定了可以将NOP激动剂的活性图谱改变为拮抗剂的分子修饰，从而产生了针对所需活性图谱的NOP配体的合理药物设计方法。我们还首次公布了NOP/阿片受体混合配体的结果，显示出作为止痛药的前景，副作用减少。在这次竞争性的更新中，我们将建立在广泛的药物化学和SAR知识的基础上，并建议在我们的配体衍生的SAR的指导下进行受体突变研究，以研究小分子NOP配体对NOP受体选择性和激活的结构要求。这一综合的多学科研究计划的目标1将使用基于配体的合理药物设计和药效团开发的方法来推动新型选择性NOP激动剂和拮抗剂的设计和合成。新化合物将通过受体结合和基于细胞的功能分析进行评估。目的2将通过使用基于受体的方法对NOP受体进行定点突变来补充这些研究，以确定参与小分子结合和激活的氨基酸。这些信息还将用于帮助设计选择性激动剂和拮抗剂。目的3研究选择性一氧化氮合酶激动剂和拮抗剂的体内作用。将确定脑渗透率，以及激动剂使用位置条件反射范式减弱阿片和可卡因奖励的能力，以及拮抗剂在急性、炎症和慢性疼痛模型中作为镇痛剂或增强阿片类止痛的能力。NOP受体已被证明在与滥用药物相关的疼痛和奖励中调节阿片类药物的作用。在这项申请中提出的工作将发现新的化合物，可以是有效的止痛药，减少耐受性和副作用，或潜在的药物滥用治疗。

DESCRIPTION (provided by applicant): The nociception receptor (NOP, previously known as the opioid receptor-like receptor ORL1) is the new, fourth member of the opioid receptor family. Although the functions of NOP and its endogenous ligand nociceptin or orphanin FQ are not well understood, this receptor system clearly plays a modulatory role in opioid-related antinociception, tolerance, and reward. These functions, in addition to the receptor's role in anxiety, learning and memory, feeding, and so on, suggest that novel small-molecule NOP ligands have potential therapeutic applications in pain, drug addiction, and other indications. In our current funding period, we discovered several novel NOP ligands and established structure-activity relationships (SAR) for binding, selectivity, and intrinsic activity for small-molecule ligands. Our SAR studies have identified molecular modifications that can change the activity profile of NOP agonists to antagonists, yielding rational drug design approaches to NOP ligands of desired activity profile. We also have the first published results of mixed NOP/opioid receptor ligands that show promise as analgesics with reduced side effects. In this competing renewal, we will build on extensive medicinal chemistry and SAR knowledge and propose receptor mutagenesis studies guided by our ligand-derived SAR to study the structural requirements for NOP receptor selectivity and activation by small molecule NOP ligands. Aim 1 of this integrated, multidisciplinary research plan will use ligand-based approaches of rational drug design and pharmacophore development to drive the design and synthesis of novel selective NOP agonists and antagonists. Novel compounds will be evaluated by receptor binding and cell-based functional assays. Aim 2 will complement these studies by using receptor-based approaches to site-directed mutagenesis of the NOP receptor to identify amino acids involved in small-molecule binding and activation. This information will also be used to aid in the design of selective agonists and antagonists. Aim 3 will investigate the in vivo actions of selective NOP agonists and antagonists. Brain penetration will be determined, as will the ability of agonists to attenuate opiate and cocaine reward using the place conditioning paradigm and the ability of antagonists to act as analgesics or potentiate opioid analgesia in acute, inflammatory, and chronic pain models. The NOP receptor has been shown to modulate opiate actions in pain and in reward associated with drugs of abuse. The work proposed in this application will discover novel compounds that can be powerful analgesics with reduced tolerance and side effects, or potential treatments for drug abuse.