PAR2 targeted drug discovery for the treatment of pain

PAR2靶向药物发现用于治疗疼痛

• 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
• 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

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。目前对慢性疼痛的治疗受到滥用可能性和难以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 (PAR2) G 蛋白偶联受体 (GPCR) 导致急性和慢性疼痛。已知 PAR2 在化学、炎症和癌症引起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，PAR2 拮抗剂在这些临床前模型中的可能功效尚未得到评估。此外，PAR2 的激活可导致多种信号传导途径的参与，但具有信号传导途径特异性功效的激动剂/拮抗剂尚未被探索作为了解 PAR2 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 PAR2 激活和信号通路特异性功效的研究对于 PAR2 配体治疗人类病理性疼痛的潜在临床开发非常重要。我们正在开发 PAR2 的新型配体，以便更好地阐明该受体在伤害感受中的作用，并开发可能具有治疗疼痛临床用途的化合物。本申请的中心假设是，PAR2 在引起急性疼痛和促进慢性疼痛方面发挥着关键作用，并且 PAR2 受体的高亲和力配体将代表一类新型镇痛药，可用于许多慢性疼痛病症。因此，该提案的主要目标是开发 PAR2 的新型特异性配体，充分阐明 PAR2 对急性和慢性疼痛的贡献，并评估 PAR2 配体作为临床前疼痛模型中新型镇痛药的功效。这些研究的成功完成将导致： 1）发现和开发新型 PAR2 激动剂/拮抗剂； 2) 确定这些新型激动剂/拮抗剂参与或减弱的信号传导途径； 3) PAR2 作为疼痛治疗重要药理学靶点的体内验证。通过这些研究，我们打算更全面地了解 PAR2 不同激动剂作用模式的生理影响，因为它与伤害感受系统相关。成功的研究将为进一步开发和测试用于治疗疼痛的 PAR2 配体提供临床前依据。这些发现代表了开发新型配体治疗人类各种病理引起的急性/慢性疼痛的重大一步。