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。

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.