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Neuropeptide FF Receptor Antagonists for Pain Treatment

用于疼痛治疗的神经肽 FF 受体拮抗剂

基本信息

批准号：
9762071
负责人：
Thuy Nguyen
金额：
$ 10.3万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762071
关键词：
Adjuvant Adverse effects Affect Affinity Amides Analgesics Attenuated Binding Biological Assay Blood - brain barrier anatomy Characteristics Chronic Clinical Cyclic AMP Dependence Development Disease Drug Kinetics Drug Targeting Effectiveness Ensure Evaluation Family G-Protein-Coupled Receptors Goals Guanidines Health Hyperalgesia In Vitro Libraries Ligands National Institute of Mental Health Opioid Opioid Analgesics Pain Pain management Penetration Peptides Permeability Pharmaceutical Preparations Positioning Attribute Process Proline Property Psychotropic Drugs Rattus Reporting Solubility Structure Structure-Activity Relationship Symptoms Therapeutic analog base chronic pain chronic pain patient chronic pain relief combat design drug candidate effective therapy expectation functional group high throughput screening improved in vitro Assay in vivo member nanomolar neuropeptide FF neuropeptide FF receptor novel novel therapeutics opioid use peptidomimetics preference radioligand receptor release of sequestered calcium ion into cytoplasm scaffold screening program side effect small molecule

项目摘要

Abstract Pain is a symptom of numerous clinical disorders that afflicts millions of people worldwide. Systemic administration of opioid analgesics remains the most effective treatment for many severe pain conditions. This class of analgesics is often associated with the development of side effects including hyperalgesia, tolerance and dependence, all of which severely limit their effectiveness in pain control. A promising strategy to combat these problems is to develop adjuvants of opioids aimed at increasing opioid efficacy and reducing opioid untoward effects. The endogenous neuropeptide FF (NPFF), a member of the RF-amide family of peptides, interacts with two distinct G protein-coupled receptors, NPFFR1 and NPFFR2. Emerging evidence indicates that NPFFR1 antagonism attenuates hyperalgesia and tolerance to opioids, two major side effects which hinder the use of opioids in pain management. Most of reported NPFFR ligands are peptides or peptidomimetics with a guanidine functional group which often has poor CNS penetration, thus not suitable for systemic administration. Recognizing the unmet need to develop potent and drug-like small molecule NPFFR1 antagonists, we have conducted a high throughput screening campaign and identified a novel proline derivative as a promising hit. Preliminary structure-activity relationship studies have improved the potencies of these compounds. In this application, we propose to further optimize this proline scaffold to improve potency, selectivity and drug-likeness.

摘要疼痛是困扰全世界数百万人的许多临床疾病的症状。系统性给予阿片类镇痛药仍然是许多严重疼痛疾病的最有效治疗方法。这一类镇痛药通常与副作用的发展有关，包括痛觉过敏、耐受性和依赖性，所有这些都严重限制了它们在疼痛控制中的有效性。一个有希望的战略，以打击开发阿片类药物的佐剂旨在增加阿片类药物的功效并减少阿片类药物的毒性。不利影响。内源性神经肽FF（NPFF）是肽的RF-酰胺家族的成员，与两种不同的G蛋白偶联受体NPFFR 1和NPFFR 2相互作用。新出现的证据表明， NPFFR 1拮抗作用减弱了痛觉过敏和对阿片类药物的耐受性，这两种主要的副作用阻碍了对阿片类药物的耐受性。阿片类药物在疼痛管理中的应用大多数已报道的NPFFR配体是肽或肽模拟物，胍官能团，其通常具有差的CNS渗透性，因此不适合全身给药。认识到开发有效的和药物样的小分子NPFFR 1拮抗剂的未满足的需求，我们进行了高通量筛选活动，并确定了一种新的脯氨酸衍生物作为一个有前途的命中。初步的构效关系研究已经提高了这些化合物的效力。在这应用中，我们建议进一步优化这种脯氨酸支架，以提高效力，选择性和药物相似性。