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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：
8237519
负责人：
Scott Boitano
金额：
$ 32.81万
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/8237519
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. PUBLIC HEALTH RELEVANCE: Chronic pain is a frequent consequence of injury or disease and impacts the lives of millions of Americans. Available treatments for chronic pain have side effects that make them untenable in many, if not most, of these cases. We propose to develop novel analgesics with increased efficacy directed at a key player in pain sensitization, the protease activated receptor-2. Such agents will be useful in elucidating the role of the protease activated receptor-2 in chronic pain states and may represent a novel therapeutic avenue for the treatment of persistent chronic pain following injury or disease.

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。目前对慢性疼痛的治疗受到滥用可能性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激活受体-2（PAR 2）G蛋白偶联受体（GPCR）而导致急性和慢性疼痛。已知PAR 2在化学、炎症和癌症诱导的疼痛中发挥重要作用，但由于缺乏可用的工具或临床候选化合物，尚未评估PAR 2拮抗剂在这些临床前模型中的可能功效。此外，PAR 2的激活可导致多种信号传导途径的参与，但尚未探索具有信号传导途径特异性功效的激动剂/拮抗剂作为理解PAR 2信号传导在伤害感受中的作用的潜在工具。评估周围神经系统中PAR 2活化和信号传导途径特异性功效的研究对于PAR 2配体用于治疗人类病理性疼痛的潜在临床开发是重要的。我们正在开发新的PAR 2配体，以更好地阐明这种受体在伤害感受中的作用，并开发可能具有临床应用的化合物用于治疗疼痛。本申请的中心假设是PAR 2在引起急性疼痛和促进慢性疼痛中起关键作用，并且PAR 2受体的高亲和力配体将代表在许多慢性疼痛病症中具有效用的新型镇痛剂。因此，本提案的主要目的是开发新型和特异性的PAR 2配体，以充分阐明PAR 2对急性和慢性疼痛的贡献，并评估PAR 2配体作为新型镇痛药在临床前疼痛模型中的功效。这些研究的成功完成将导致：1）PAR 2的新型激动剂/拮抗剂的发现和开发; 2）这些新型激动剂/拮抗剂参与或减弱的信号传导途径的确定;和3）PAR 2作为疼痛治疗的重要药理学靶标的体内验证。从这些研究中，我们打算获得一个更完整的了解不同模式的激动剂作用在PAR 2的生理后果，因为它涉及到伤害性系统。成功的研究将为进一步开发和测试用于治疗疼痛的PAR 2配体提供临床前理论基础。这些发现代表了在开发新型配体以治疗人类各种病理学引起的急性/慢性疼痛方面的重大进展。慢性疼痛是伤害或疾病的常见后果，影响着数百万美国人的生活。现有的慢性疼痛治疗方法有副作用，使他们在许多情况下，如果不是大多数，这些情况下站不住脚。我们建议开发新的镇痛药，针对疼痛致敏的关键参与者，蛋白酶激活受体-2具有更高的疗效。这类药物可用于阐明蛋白酶激活受体-2在慢性疼痛状态中的作用，并可能代表治疗损伤或疾病后持续性慢性疼痛的新治疗途径。