DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

描述（由申请人提供）：痛觉受体（NOP，以前称为阿片受体样受体ORL1）是阿片受体家族的新成员。虽然NOP及其内源性配体痛觉肽或孤啡肽FQ的功能尚不清楚，但该受体系统在阿片类药物相关的抗痛觉、耐受和奖励中明显发挥调节作用。这些功能，加上受体在焦虑、学习记忆、进食等方面的作用，表明新的小分子NOP配体在疼痛、药物成瘾和其他适应症中具有潜在的治疗应用。在我们目前的资助期内，我们发现了几种新的NOP配体，并建立了小分子配体的结合、选择性和固有活性的结构-活性关系（SAR）。我们的SAR研究已经确定了可以将NOP激动剂的活性谱改变为拮抗剂的分子修饰，从而为期望活性谱的NOP配体提供了合理的药物设计方法。我们也首次发表了混合NOP/阿片受体配体的研究结果，这些配体有望作为减少副作用的镇痛药。在这个竞争性的更新中，我们将建立广泛的药物化学和SAR知识，并提出受体诱变研究，以我们的配体衍生的SAR为指导，研究小分子NOP配体对NOP受体选择性和激活的结构要求。这个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方法来驱动新型选择性NOP激动剂和拮抗剂的设计和合成。新的化合物将通过受体结合和基于细胞的功能分析来评估。目的2将利用基于受体的方法对NOP受体进行定点诱变，以确定参与小分子结合和激活的氨基酸，从而对这些研究进行补充。这些信息也将用于帮助设计选择性激动剂和拮抗剂。目的3将研究选择性NOP激动剂和拮抗剂的体内作用。在急性、炎症和慢性疼痛模型中，脑穿透将被确定，激动剂使用场所条件反射范式减弱阿片和可卡因奖励的能力以及拮抗剂作为镇痛药或增强阿片镇痛的能力也将被确定。NOP受体已被证明可以调节阿片类药物在与滥用药物相关的疼痛和奖励中的作用。本应用程序中提出的工作将发现新的化合物，这些化合物可以作为强效镇痛药，减少耐受性和副作用，或潜在的药物滥用治疗方法。

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.