DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

描述（由申请人提供）：伤害感受受体（NOP，以前称为阿片受体样受体ORL 1）是阿片受体家族的第四个新成员。虽然NOP及其内源性配体痛敏肽或Nociceptin在FQ中的功能还不清楚，但该受体系统显然在阿片相关的抗伤害感受、耐受和奖赏中起着调节作用。除了受体在焦虑、学习和记忆、进食等方面的作用之外，这些功能表明新型小分子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间，我们发现了几种新型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SAR研究已经确定了可以将NOP激动剂的活性特征改变为拮抗剂的分子修饰，从而得到具有所需活性特征的NOP配体的合理药物设计方法。我们还首次发表了混合NOP/阿片受体配体的结果，这些结果显示出作为镇痛剂的希望，副作用减少。在这一竞争性更新中，我们将建立在广泛的药物化学和SAR知识的基础上，并提出由我们的配体衍生SAR指导的受体诱变研究，以研究小分子NOP配体对NOP受体选择性和活化的结构要求。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。新化合物将通过受体结合和基于细胞的功能测定进行评价。目标2将通过使用基于受体的方法对NOP受体进行定点诱变以鉴定参与小分子结合和活化的氨基酸来补充这些研究。该信息也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NOP激动剂和拮抗剂的体内作用。将确定脑渗透，以及激动剂使用位置条件反射范例减弱阿片和可卡因奖赏的能力，以及拮抗剂在急性、炎性和慢性疼痛模型中充当镇痛剂或增强阿片类镇痛的能力。NOP受体已被证明可调节阿片类药物在疼痛和与药物滥用相关的奖赏中的作用。本申请中提出的工作将发现新的化合物，这些化合物可以是具有降低的耐受性和副作用的强效镇痛剂，或者是药物滥用的潜在治疗方法。

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.