ChemR23 agonists for pain and inflammation

ChemR23 激动剂治疗疼痛和炎症

• 批准号: 8122730
• 负责人: Miguel Garcia-Guzman
• 金额: $ 41.75万
• 依托单位: ASPYRIAN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122730
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Adverse effects; Agonist; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Antiepileptic Agents; Arrestins; Biological Assay; CYP2D6 gene; CYP3A4 gene; Cell Line; Cells; Chemicals; Chronic Disease; Clinical; Collaborations; Coupling; Coxibs; Cyclic AMP; Developed Countries; Development; Disease; Dose; Evaluation; Future; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Housing; Human; Hyperalgesia; Inflammation; Label; Lead; Ligands; Lipids; Measures; Medical; Membrane; Metabolic; Microsomes; Mus; Narcotics; Neuronal Plasticity; Neurons; Non-Steroidal Anti-Inflammatory Agents; Pain; Pain Nature; Pain management; Pathology; Pathway interactions; Permeability; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Process; Property; Protein Kinase; Rattus; Recombinants; Resolution; Risk; Safety; Screening procedure; Series; Signal Pathway; Signal Transduction; Societies; Solubility; Specificity; System; Technology; Testing; Validation; Work; addiction; allodynia; analog; base; chemical property; chronic pain; clinically relevant; cost; desensitization; disability payment; high throughput screening; in vivo; innovation; lead series; lipid mediator; macrophage; novel; novel strategies; pre-clinical; productivity loss; programs; receptor; receptor internalization; release of sequestered calcium ion into cytoplasm; response; scaffold; small molecule; small molecule libraries; therapy development; transmission process

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.

描述（由申请人提供）：疼痛给社会带来了巨大的负担，在发达国家，每年在医疗、生产力损失和残疾赔偿方面花费约1万亿美元，更不用说与中度至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。麻醉品造成成瘾和安全风险的问题，而其他类型的止痛药（例如NSAID、COX 2抑制剂、抗抑郁药和抗癫痫药）则因疗效有限和急性或长期副作用而受到阻碍。此外，认识到疼痛的进行性，由于慢性疾病（例如炎症）的存在和参与疼痛的神经元机制的可塑性，疼痛演变为持续性异常性疼痛和痛觉过敏，需要开发具有疾病修饰潜力的新型镇痛治疗。未来的治疗应该解决疼痛传递（镇痛活性），同时改善疼痛的原因（例如炎症）和逆转异常神经元变化引起的异常性疼痛和痛觉过敏。最近发现，称为resolvins的脂质介质激活ChemR23 G蛋白偶联受体以诱导镇痛，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疗法提供了独特的机会。我们提出了一种创新的方法来确定新的ChemR23小分子激动剂，通过使用新的功能筛选技术的基础上标记的形式，和信号转导分析，以选择和优化具有最佳药理学特征的分子。考虑到消退素作为抗炎配体的临床验证以及ChemR23镇痛机制与临床相关过程的相关性，ChemR23激动剂可能代表治疗急性和慢性疼痛病症的新型镇痛药。 公共卫生相关性：迫切需要开发安全且诱导有效镇痛同时逆转引起痛觉过敏和异常性疼痛的病理学的新型疼痛治疗。该提案详细介绍了一种基于新的作用机制开发新型疼痛治疗方法的新方法，该机制具有诱导镇痛，改善炎症和逆转导致和维持慢性疼痛的神经元改变的潜力。在该项目中开发的药物产品可能在疼痛管理方面具有变革性，具有慢性疼痛疾病修饰作用的潜力。