A NOVEL APPROACH FOR PAIN TREATMENT WITHOUT OPIOID LIABILITIES

一种没有阿片类药物副作用的疼痛治疗新方法

基本信息

批准号：
9270527
负责人：
Nurulain T Zaveri
金额：
$ 73.6万
依托单位：
ASTRAEA THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9270527
关键词：
Absence of pain sensation Acute Pain Adult Adverse effects Affect African American Agonist American Analgesics Animal Model Biological Assay Biological Availability Brain Capsaicin Child Chronic Clinical Clinical Trials Constipation Data Development Disease Dose Drug Kinetics Effectiveness Evaluation Family Future Hispanics Human Hyperalgesia Hypoxia In Vitro Inflammatory Ion Channel Lead Life Ligands Manuscripts Metabolic Modality Modeling Modification Monkeys Morphine Mus Narcotic Antagonists National Institute of Neurological Disorders and Stroke Nausea Opioid Opioid Analgesics Opioid Receptor Oral Pain Pain Research Pain management Pathway interactions Patients Penetration Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Plasma Productivity Public Health Quality of life Research Rewards Rodent Rodent Model Safety Sickle Cell Anemia Solid Spinal Cord Symptoms Testing Therapeutic Time Toxic effect Transgenic Mice Transgenic Organisms United States Work allodynia base chronic pain cost cytokine delta opioid receptor design drug candidate drug development effective therapy experience improved in vivo inflammatory pain mast cell member mouse model mu opioid receptors nociceptin nonhuman primate novel novel strategies painful neuropathy patch clamp phase 1 study pre-clinical preclinical development preference public health relevance receptor receptor binding sickling small molecule standard of care translational study

项目摘要

DESCRIPTION (provided by applicant): Every year, about 100 million adult Americans experience some form of pain, a condition that costs the nation between $560 billion and $635 billion annually in lost productivity and treatment. The recently released `National Pain Strategy' developed by the NINDS's IPRCC, recognizes acute and chronic pain as a serious and costly public health issue, and articulates that new treatment approaches need to be developed to reduce the burden of pain in the US. Opioid analgesics are the mainstay of pain treatment and often the only treatment option that provides significant relief. However, opioid analgesics (which are mainly mu opioid receptor (MOP) agonists) are controlled substances that have abuse potential and are riddled with other side effects such as constipation, nausea, and tolerance, which impede their long-term safety and effectiveness. There is clearly a need for new analgesics that provide opioid-like efficacies without the liabilities of opioid pain-killers. he nociceptin opioid receptor (NOP), the 4th member of the opioid receptor family, and its endogenous peptide ligand, nociceptin/orphanin FQ (N/OFQ) are emerging new targets for pain medications. The NOP receptor and N/OFQ are found throughout in pain-processing pathways in the brain and spinal cord, and modulate opioid function by blocking opioid reward and even tolerance. We and others have shown that the natural peptide N/OFQ and small-molecule NOP agonists and bifunctional' NOP agonists with mu opioid agonist activity show potent analgesic effects on acute and chronic pain, are non-rewarding and do not develop tolerance. These findings suggest that NOP receptor agonists may be an attractive approach to obtain potent analgesic efficacies without opioid-related liabilities. In our Phase I project, we investigated th analgesic potential of NOP agonists in a transgenic mouse model of `sickle cell disease'(SCD), which develops spontaneous hyperalgesia similar to the condition in sickle patients. SCD is associated with severe pain, which remains a major challenge to treat. Opioids are the current standard of care, but due to side effects and development of tolerance, remain a sub-optimal approach to treat SCD pain, particularly when needed on a continued basis. Development of effective analgesics devoid of opioid liabilities would have a significant impact on pain treatment in SCD. Our Phase I studies showed that the NOP agonist-mu low efficacy agonist AT-200 showed significant antinociceptive efficacy in sickle mice, more potent and longer-lasting than high-dose morphine. AT-200 also showed a sustained analgesic effect, without tolerance development. These promising data that NOP agonists and/or NOP-mu bifunctional agonists are promising analgesics for treating chronic pain such as sickle pain. In this Phase II project we propose to conduct lead optimization and medicinal chemistry to identify novel NOP-targeted `preclinical lead candidates', which are optimized for their drug-like suitability and novelty, hav in vivo efficacy in pain models in rodents and nonhuman primates, and preliminary evaluation of toxicity, that are ready to be advanced into IND-enabling studies for development as pain medications.

描述（由适用提供）：每年，约有1亿成年美国人会经历某种形式的痛苦，这种情况每年损失生产力和治疗，使该国每年损失5600亿至6350亿美元。 Ninds的IPRCC最近发布的“国家疼痛策略”（National Pain Strategy）是一个严重且昂贵的公共卫生问题，并阐明需要开发出新的治疗方法来减轻美国疼痛的燃烧。阿片类镇痛药是疼痛治疗的支柱，通常是唯一可提供明显缓解的治疗选择。但是，阿片类镇痛药（主要是MU阿片受体（MOP）激动剂）是受滥用潜力的受控物质，并受到其他副作用（例如便秘，恶心和耐受）的束缚，这会阻碍其长期的安全性和有效性。显然，需要新的镇痛药，这些镇痛药可提供类似阿片类药物的效率，而无需阿片类止痛药的责任。 NociTptin阿片受体（NOP），阿片受体家族的第四个成员及其内源性肽配体，Nocceptin/Orphanin FQ（N/OFQ）是疼痛药物的新靶标。 NOP受体和N/OFQ始终在大脑和脊髓中的疼痛处理途径中发现，并通过阻止蛋白质奖励甚至耐受性来调节阿片类药物功能。我们和其他人表明，具有mu oopioid激动剂活性的天然肽N/OFQ和小分子NOP激动剂以及双功能的“ NOP激动剂”对急性和慢性疼痛表现出潜在的镇痛作用，是非奖励的，并且不产生耐受性。这些发现表明，NOP受体激动剂可能是一种有吸引力的方法，可以获得无骨相关责任的潜在镇痛作用。我们的第一阶段项目，我们研究了NOP激动剂在“镰状细胞疾病”（SCD）的转基因小鼠模型中的镇痛潜力，该模型会发展出与镰状患者病情相似的赞助性痛觉过敏。 SCD与严重的疼痛有关，这仍然是治疗的主要挑战。阿片类药物是目前的护理标准，但是由于副作用和耐受性的发展，仍然是治疗SCD疼痛的亚最佳方法，尤其是在需要的情况下。开发没有阿片类药物负债的有效镇痛药将对疼痛治疗产生重大影响在SCD中。我们的I阶段研究表明，NOP激动剂-MU低效率激动剂在200上表现出显着的抗伤害感受效率，比高剂量吗啡的潜在潜力和持久性更大。 AT-200还显示出持续的镇痛作用，没有耐受性的发展。这些有前途的数据表明，NOP激动剂和/或NOP-MU双功能激动剂是有望治疗慢性疼痛（例如镰状疼痛）的镇痛药。这个第二阶段项目我们提议进行铅优化和医学化学，以识别新颖的NOP靶向“临床前铅候选者”，这些临床前候选者对它们的药物样和新颖性和新颖性，在啮齿动物和非人类隐私中的疼痛模型中的体内效率以及对毒性的初步评估，这些效率已随时可以通过促进性疗法进行疼痛药物进行。