Development of Novel Neuropeptide B/W Receptor 1 Agonists

新型神经肽B/W受体1激动剂的开发

基本信息

批准号：
10047390
负责人：
Thuy Nguyen
金额：
$ 21.46万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047390
关键词：
4-nitrophenethyl bromide Affinity Agonist Alanine Amino Acids Amygdaloid structure Analgesics Anatomy Anxiety Binding Biological Assay Biological Availability Biological Pharmacology Biological Process Cell Line Cell Membrane Permeability Cells Chemicals Data Development Diabetes Mellitus Drug Targeting Emotions Energy Metabolism Epilepsy Essential Amino Acids Evaluation Family Feeding behaviors Fright Future G-Protein-Coupled Receptors Genes Human Immune Inflammatory Knockout Mice Length Libraries Ligands Mediating Membrane Proteins Metabolic Modification Molecular N-terminal NPBWR1 gene Names Neuropathy Neuropeptides Nociception Obesity Opioid Receptor Opioid agonist Pain Pain management Pathologic Patients Peptides Peripheral Nerves Pharmaceutical Preparations Pharmacology Physiological Preparation Protein Isoforms Proteolysis Receptor Activation Regulation Reporting Research Resistance Rodent Role Sampling Scanning Seizures Series Side Signal Transduction Source Structure System Techniques Testing Therapeutic Triage base blood-brain barrier permeabilization cost efficient design drug development improved in vivo innovation insight kappa opioid receptors mimetics neuropeptide B novel opioid epidemic overexpression peptidomimetics preservation prevent receptor release of sequestered calcium ion into cytoplasm response scaffold screening small molecule therapeutic candidate therapeutic development tool

项目摘要

Abstract G protein-coupled receptors (GPCRs) are a major family of targets for drug development; however, only a small number of GPCRs have successfully provided drugs on the market and many remain understudied for therapeutic applications. A lack of suitable tool compounds is a major obstacle to understand physiological functions of these understudied GPCRs. Neuropeptide B/W Receptor 1 (NPBWR1) has been suggested to hold great potential for several therapeutic applications, particularly for pain treatment based on its overexpression in patients' samples and in vivo studies using endogenous neuropeptides. Due to their metabolic instability and poor membrane permeability, these native neuropeptides require central administration, making them unsuitable for therapeutics development. Till date, no small molecule agonists have been discovered yet. Recognizing the unmet need to develop more stable and druglike tool compounds to facilitate research on this promising target, we propose to develop NPBWR1 agonists using a two-pronged approach, peptidomimetic design and repurposing opioid receptor ligands.

抽象的 G 蛋白偶联受体 (GPCR) 是药物开发的一个主要靶标家族；然而，只有一小部分许多 GPCR 已成功将药物推向市场，并且许多药物仍在研究中治疗应用。缺乏合适的工具化合物是理解生理学的主要障碍这些正在研究的 GPCR 的功能。神经肽 B/W 受体 1 (NPBWR1) 建议保留多种治疗应用的巨大潜力，特别是基于其过度表达的疼痛治疗患者样本和使用内源性神经肽的体内研究。由于其代谢不稳定和由于膜渗透性差，这些天然神经肽需要中枢给药，因此不适合用于治疗方法的开发。迄今为止，尚未发现小分子激动剂。认识到开发更稳定和类似药物的工具化合物以促进对这一有希望的目标的研究尚未得到满足，我们建议采用双管齐下的方法开发 NPBWR1 激动剂，即肽模拟设计和重新利用阿片受体配体。