DISCOVERY OF SMALL-MOLECULE ORPHANIN FQ RECEPTOR LIGANDS

小分子孤啡肽 FQ 受体配体的发现

基本信息

批准号：
7681519
负责人：
Nurulain T Zaveri
金额：
$ 19.89万
依托单位：
ASTRAEA THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681519
关键词：
Absence of pain sensation Acute Adverse effects Affect Affinity Agonist Alcohol abuse Amino Acids Analgesics Anxiety Attenuated Binding Biological Assay Brain Cells Chimera organism Chronic inflammatory pain Circadian Rhythms Cocaine Complement Development Dimensions Drug Addiction Drug Design Drug abuse Family Foundations Functional disorder Funding G-Protein-Coupled Receptors Grant Interdisciplinary Study Investigation Kidney Knowledge Lead Learning Legal patent Ligands Literature Memory Modeling Modification Molecular Morphine Mutagenesis Names Nitrogen Nociception ORL1 receptor Opiates Opioid Opioid Receptor Pain Pathway interactions Penetration Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Play Publishing Reporting Research Research Personnel Rewards Role Series Site-Directed Mutagenesis Structural Models Structure Structure-Activity Relationship Subcutaneous Injections System Therapeutic Work addiction base brain tissue chronic pain conditioning design drug of abuse feeding improved in vivo member molecular recognition multidisciplinary nociceptin nociceptin receptor novel pharmacophore piperidine receptor receptor binding scaffold small molecule tool

项目摘要

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.

描述（由申请人提供）：伤害受体（NOP，以前称为阿片受体样受体ORL1）是阿片类受体家族的新的第四个成员。尽管NOP及其内源性配体nocteptin或Orphanin FQ的功能尚不清楚，但该受体系统在阿片类药物相关的抗伤害感受，耐受性和奖励中显然起着调节作用。除了受体在焦虑，学习和记忆，喂养等中的作用外，这些功能还表明，新型的小分子NOP配体在疼痛，药物成瘾和其他适应症中还具有潜在的治疗应用。在当前的资助期间，我们发现了几种新型的NOP配体，并建立了结构性关系（SAR），用于结合，选择性和小分子配体的内在活性。我们的SAR研究已经确定了可以改变NOP激动剂到拮抗剂的活性特征的分子修饰，从而为所需活性谱的NOP配体提供了合理的药物设计方法。我们还拥有混合NOP/阿片类受体配体的首次发表的结果，这些结果表现为镇痛药，副作用减少。在这种竞争的更新中，我们将以广泛的药物化学和SAR知识为基础，并提出以我们的配体衍生SAR指导的受体诱变研究，以研究小分子NOP配体的NOP受体选择性和激活的结构要求。该综合，多学科研究计划的目标1将采用基于配体的理性药物设计和药剂团发育的方法来推动新颖的选择性NOP激动剂和拮抗剂的设计和综合。新型化合物将通过受体结合和基于细胞的功能测定评估。 AIM 2将通过使用基于受体的方法来补充这些研究的NOP受体定位诱变，以鉴定涉及小分子结合和激活的氨基酸。该信息还将用于帮助设计选择性激动剂和拮抗剂。 AIM 3将研究选择性NOP激动剂和拮抗剂的体内作用。将确定脑穿透力，激动剂使用该地点调节范式减弱鸦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充当镇痛药或增强阿片类镇痛的能力。 NOP受体已被证明可以调节痛苦中的鸦片作用，并与滥用药物有关。本应用程序中提出的工作将发现新颖的化合物，这些化合物可以是强大的镇痛药，其耐受性和副作用降低，或者对药物滥用的潜在治疗方法。