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

• 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
• 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

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.

摘要 G蛋白偶联受体（GPCR）是药物开发的主要靶标家族;然而，只有一小部分GPCR被用于药物开发。 许多GPCR已经成功地在市场上提供了药物，其中许多仍然没有得到充分的研究， 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。 这些未充分研究的GPCR的功能。神经肽B/W受体1（NPBWR 1）被认为是 在几种治疗应用中具有巨大的潜力，特别是基于其在神经元中的过表达用于疼痛治疗。 患者的样本和使用内源性神经肽的体内研究。由于他们的新陈代谢不稳定， 由于膜通透性差，这些天然神经肽需要中枢给药， for therapeutic治疗development发展.迄今为止，尚未发现小分子激动剂。认识到 未满足的需要是开发更稳定和药物样的工具化合物以促进对该有希望的靶点的研究， 我们建议使用双管齐下的方法开发NPBWR 1激动剂，肽模拟物设计和 重新利用阿片受体配体。