ChemR23 agonists for pain and inflammation

描述(申请人提供)：疼痛给社会带来了巨大的负担，在发达国家，每年在医疗、生产力损失和残疾抚恤金方面的成本约为1万亿美元，更不用说与中到重度急性和慢性疼痛相关的人类痛苦。目前的治疗方法不足以应对急性和慢性疼痛的挑战。麻醉药品造成成瘾和安全风险问题，而其他类型的止痛药(如非类固醇抗炎药、COX2抑制剂、抗抑郁药和抗癫痫药)因疗效有限和急性或长期副作用而受到阻碍。此外，由于慢性疾病(如炎症)的存在以及与疼痛相关的神经元机制的可塑性，对疼痛进行性本质的认识要求开发具有改善疾病潜力的新的止痛治疗方法。未来的治疗方法应该针对疼痛传递(止痛活性)，同时改善疼痛的原因(例如炎症)，并逆转导致痛觉过敏和痛觉过敏的异常神经元变化。最近的发现，称为解决素的脂质介质，激活ChemR23 G蛋白偶联受体来诱导镇痛，改善炎症，并逆转与慢性疼痛相关的神经元可塑性，这为开发具有转化潜力的治疗方法提供了一个独特的机会。我们提出了一种创新的方法来识别新的ChemR23小分子激动剂，通过使用基于无标记格式的新功能筛选技术和信号转导分析来选择和优化具有最佳药理特征的分子。考虑到解决素作为抗炎配体的临床有效性，以及ChemR23的止痛机制与临床相关过程的相关性，ChemR23激动剂可能代表着一类新的止痛药，用于治疗急慢性疼痛。 与公共卫生相关：迫切需要开发安全的新的疼痛治疗方法，在逆转导致痛觉过敏和超敏的病理的同时，诱导有效的止痛。这项提议详细介绍了一种新的方法来开发基于新的作用机制的新的疼痛治疗方法，该新的作用机制具有诱导止痛、改善炎症和逆转导致和持续慢性疼痛的神经元变化的潜力。在该计划中开发的药物产品可能在疼痛管理方面具有变革性，具有改善慢性疼痛的疾病作用的潜力。

DESCRIPTION (provided by applicant): Pain imposes a tremendous burden on society, costing approximately US$1 trillion per year in medical treatment, loss of productivity and disability payments in developed countries, not to mention the human suffering associated with moderate to severe acute and chronic pain. Current treatments are insufficient to address the challenge of acute and chronic pain. Narcotics pose a problem of addiction and safety risk while other types of analgesics (e.g. NSAIDs, COX2 inhibitors, antidepressants and anti-epileptics) are hampered by limited efficacy and acute or long-term side effects. Moreover, the recognition of the progressive nature of pain, with pain evolving into persistent allodynia and hyperalgesia due to the presence of chronic disease (e.g. inflammation) and plasticity of neuronal mechanisms involved in pain, calls for the development of novel analgesic treatments with disease modifying potential. Future therapies should address pain transmission (analgesic activity) while ameliorating the cause of pain (e.g. inflammation) and reversing the abnormal neuronal changes causing allodynia and hyperalgesia. The recent discovery that lipid-mediators called resolvins, activate ChemR23 G-protein coupled receptors to induce analgesia, ameliorate inflammation, and reverse neuronal plasticity associated with chronic pain presents a unique opportunity to develop therapies with transformational potential. We propose an innovative approach to identify novel ChemR23 small molecule agonists by using new functional screening technologies based on label free formats, and signal transduction analysis to select and optimize molecules with optimal pharmacological profiles. Given the clinical validation of resolvins as anti-inflammatory ligands and the correlation of ChemR23 mechanisms of analgesia with processes of clinical relevance, ChemR23 agonists may represent a novel new class of analgesics to treat acute and chronic pain conditions. PUBLIC HEALTH RELEVANCE: There is a critical medical need to develop novel treatments for pain that are safe and induce effective analgesia while reversing the pathology causing hyperalgesia and allodynia. This proposal details a new approach to develop novel pain treatments based on a new mechanism of action that has the potential to induce analgesia, ameliorate inflammation and reverse neuronal alterations that lead to and sustain chronic pain. Drug products developed in this program could be transformative in pain management with the potential of disease modifying actions in chronic pain.