PAR2 targeted drug discovery for the treatment of pain

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潜在滥用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）参与急性和慢性疼痛。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疗效尚未得到评估。此外，PAR2的激活可导致多种信号通路的参与，但具有信号通路特异性功效的激动剂/拮抗剂尚未被探索作为理解PAR2信号通路在伤害感觉中的作用的潜在工具。评估PAR2在周围神经系统中的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具有重要意义。我们正在开发新的PAR2配体，以更好地阐明该受体在伤害感觉中的作用，并开发可能具有临床治疗疼痛效用的化合物。该应用的中心假设是PAR2在引起急性疼痛和促进慢性疼痛中起关键作用，并且PAR2受体的高亲和力配体将代表一类新型镇痛药，在许多慢性疼痛条件下具有实用性。因此，本研究的主要目标是开发新的特异性PAR2配体，充分阐明PAR2在急性和慢性疼痛中的作用，并在临床前疼痛模型中评估PAR2配体作为新型镇痛药的疗效。这些研究的成功完成将导致：1)发现和开发新的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通路；3)体内验证PAR2作为治疗疼痛的重要药理靶点。从这些研究中，我们打算更全面地了解PAR2中不同激动剂作用模式的生理后果，因为它与伤害感觉系统有关。成功的研究将为进一步开发和测试PAR2配体治疗疼痛提供临床前基础。这些发现代表了新型配体治疗人类各种病理引起的急性/慢性疼痛的重要一步。

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.