PAR2 targeted drug discovery for the treatment of pain

PAR2靶向药物发现用于治疗疼痛

基本信息

批准号：
8543773
负责人：
Scott Boitano
金额：
$ 31.64万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8543773
关键词：
Acute Acute Pain Adverse effects Afferent Neurons Affinity Agonist American Analgesics Attenuated Binding Biological Assay Bypass Cell model Chemicals Chronic Clinical Data Development Disease Epithelial Europium Event Fluorescence G-Protein-Coupled Receptors GTP-Binding Proteins Goals Human In Vitro Inflammatory Injury Label Laboratories Lead Ligands MAP Kinase Gene Malignant Bone Neoplasm Malignant Neoplasms Measures Modeling Molecular Molecular Models Mus Nociception Nociceptors PAR-2 Receptor Pain Pain management Pathology Pathway interactions Pentetic Acid Peptide Hydrolases Peptides Peripheral Nervous System Pharmaceutical Preparations Pharmacology Physiological Play Pre-Clinical Model Role Signal Pathway Signal Transduction Specificity Structure-Activity Relationship System Techniques Testing Thermal Hyperalgesias Time Transgenic Mice Validation base cell analyzer chronic pain drug discovery high throughput screening high throughput technology in vivo molecular modeling mouse model nervous system disorder novel novel therapeutics peptidomimetics pre-clinical receptor scaffold seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide time use tool

项目摘要

DESCRIPTION (provided by applicant): Chronic pain is a neurological disorder that impacts the lives of millions of Americans. Current treatments for chronic pain are limited by abuse potential and intolerable side effects. Endogenous proteases contribute to acute and chronic pain through the direct activation of the protease activated receptor-2 (PAR2) G-protein coupled receptor (GPCR). PAR2 is known to play an important role in chemical, inflammatory and cancer-induced pain but the possible efficacy of PAR2 antagonists in these preclinical models has not been assessed due to lack of available tools or clinical candidate compounds. Moreover, activation of PAR2 can lead to engagement of multiple signaling pathways yet agonists/antagonists with signaling pathway specific efficacy have not been explored as potential tools for understanding the role of PAR2 signaling in nociception. Studies assessing PAR2 activation and signaling pathway specific efficacy in the peripheral nervous system are important for the potential clinical development of PAR2 ligands for the treatment of pathological pain in humans. We are developing novel ligands to PAR2 in an effort to better elucidate the role of this receptor in nociception and to develop compounds that may have clinical utility for the treatment of pain. The central hypothesis of this application is that PAR2 plays a pivotal role in causing acute pain and promoting chronic pain and that high affinity ligands of the PAR2 receptor will represent a novel class of analgesics with utility in a number of chronic pain conditions. Thus, the primary objectives of this proposal are to develop novel and specific ligands to PAR2, to fully elucidate PAR2 contribution to acute and chronic pain, and to evaluate PAR2 ligand efficacy as novel analgesics in preclinical pain models. Successful completion of these studies will result in: 1) the discovery and development of novel agonists/antagonists for PAR2; 2) determination of signaling pathways that are engaged or attenuated by these novel agonists/antagonists; and 3) in vivo validation of PAR2 as an important pharmacological target for pain treatment. From these studies we intend to gain a more complete understanding of the physiological ramifications of different modes of agonist action at PAR2 as it relates to the nociceptive system. Successful studies will provide a preclinical rationale for the further development and testing of PAR2 ligands for the treatment of pain. Such findings represent a major step forward in the development of novel ligands to treat acute/chronic pain that can result from a variety of pathologies in humans.

描述（由申请人提供）：慢性疼痛是一种影响数百万美国人生活的神经系统疾病。当前对慢性疼痛的治疗受到滥用潜力和无法忍受的副作用的限制。内源性蛋白酶通过直接激活蛋白酶活化受体-2（PAR2）G蛋白偶联受体（GPCR）导致急性和慢性疼痛。众所周知，PAR2在化学，炎症和癌症引起的疼痛中起着重要作用，但是由于缺乏可用的工具或临床候选化合物，尚未评估PAR2拮抗剂在这些临床前模型中的可能功效。此外，PAR2的激活可以导致多个信号通路的参与度，但尚未将具有信号途径特定功效的激动剂/拮抗剂作为理解PAR2信号在伤害感受吸引力中的作用的潜在工具。评估PAR2激活和信号通路途径的研究对外周神经系统中的特异性功效对于对治疗人类病理疼痛的PAR2配体的潜在临床发育至关重要。我们正在为PAR2开发新型的配体，以更好地阐明该受体在伤害感受中的作用，并开发可能具有临床效用的化合物来治疗疼痛。该应用的中心假设是，PAR2在引起急性疼痛和促进慢性疼痛方面起着关键作用，而PAR2受体的高亲和力配体将代表一类新型的镇痛药，并在许多慢性疼痛条件下实用。因此，该提案的主要目标是将新颖和特定的配体开发为PAR2，以完全阐明PAR2对急性和慢性疼痛的贡献，并评估PAR2配体功效为临时性疼痛模型中的新型镇痛药。这些研究的成功完成将导致：1）PAR2的新型激动剂/拮抗剂的发现和发展； 2）确定这些新型激动剂/拮抗剂所参与或衰减的信号通路； 3）体内验证PAR2是疼痛治疗的重要药理靶标。从这些研究中，我们打算更完整地了解与伤害性系统相关的不同激动剂作用模式的生理后果。成功的研究将为PAR2配体的进一步发展和测试提供临床前原理，以治疗疼痛。这些发现代表了新型配体的发展迈出的重要一步，以治疗急性/慢性疼痛，这可能是由于人类的多种病理而引起的。