DEVELOPMENT OF NOCICEPTIN-BASED ANALGESICS

基于伤害肽的镇痛药的开发

• 批准号: 6476229
• 负责人: AMRIT K JUDD
• 金额: $ 39.02万
• 依托单位: SYNVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476229
• 关键词: analgesics; blood brain barrier; chemical structure function; chemical synthesis; chronic pain; computer simulation; diabetic neuropathy; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; laboratory rat; mathematical model; nociceptin; opioid receptor; pain; peptide analog; stimulant /agonist

The goal of the proposed project is to develop a nonaddicting analgesic for chronic and acute pain. There is an urgent need for effective treatments for chronic, neuropathic pain, a relatively common complication of diabetes. As diabetic neuropathy progresses, neuropathic pain becomes increasingly difficult to treat with currently available analgesics such as anti-depressants and opioids. Morphine and its analogs are routinely prescribed, inspite of their side effects, because good analgesics are currently not available. Newly identified nociceptin and its analgesic activity in animal studies provide a potential target for the relief of chronic and neuropathic pain. Because the nociceptin antagonist does not act through opiate receptor, addiction and opioidrelated side effects may not be a problem. However, because of its size (17 amino acid) and peptidic nature, nociceptin is not going to make it as a therapeutic agent; a small non-peptide analog will be required to commercialize any compound. During Phase I studies, we were able to identify a group of small derivatized hex peptides with high binding affinity to human ORL I receptor. In addition, we were able to identify potent analogs with functional activity ranging from nearly a full agonist to a complete antagonist, at least 10 times more potent than the reported antagonist. Our antagonist-derivatized peptide has been shown to potentate morphine analgesia and possesses some analgesic activity on its own. Our derivatized haxapeptides have great potential as analgesics and the findings of Phase I will form the basis for the further development of a nonaddicting analgesic for chronic and acute pain. The specific aims for Phase II are: (I) Design non-peptide analogs of potent derivatized hex peptides to enhance potency, efficacy, and half-life. Conduct computational experiments to design these analogs. (ii) Conduct in vitro experiments to study binding affinity. (iii) Conduct functional assay on high affinity compounds to determine agonist and antagonist activity. (iv) Conduct in vivo experiments on high affinity agonists and antagonists for analgesic or nociceptive activity. (v) Conduct in vivo experiments on the most effective agonist and antagonist to determine their actions in chronic pain modes. The data generated by these studies will provide important information to bring this technology to a level of maturity where it can compete successfully for commercial funding to bring an effective therapeutic agent to clinical use. PROPOSED COMMERCIAL APPLICATION: Non-peptide analogs of nociceptin, prepared under this program, will be developed into therapeutics that can be used for the treatment of chronic and neuropathic pain. For this type of debilitating chronic injury, there is no suitable treatment available currently. Market opportunity for analgesics is worth in excess of $5 billion and is growing rapidly. The development of non-peptide agonists would likely add effective compounds for this enormous market.

拟议项目的目标是开发一种用于慢性疼痛的非成瘾性镇痛药 和急性疼痛。 迫切需要有效治疗慢性神经病 疼痛，一种相对常见的糖尿病并发症。由于糖尿病神经病变 随着病情的进展，神经性疼痛变得越来越难以治疗 目前可用的止痛药如抗抑郁药和阿片类药物。吗啡 及其类似物尽管有副作用，但仍被常规使用， 因为目前还没有好的止痛药。新发现的 伤害感受肽及其在动物研究中的镇痛活性提供了潜在的 缓解慢性和神经性疼痛的目标。因为伤害感受肽 拮抗剂不通过阿片受体发挥作用，成瘾与阿片类药物相关 副作用可能不是问题。然而，由于其大小（17 个氨基酸） 和肽性质，伤害感受肽不会将其用作治疗剂； 任何化合物的商业化都需要一种小的非肽类似物。 在第一阶段研究期间，我们能够识别出一组小型衍生化药物 与人 ORL I 受体具有高结合亲和力的六肽。此外， 我们能够鉴定出具有以下功能活性的有效类似物： 几乎是完全拮抗剂的完全激动剂，效力至少高出 10 倍 比报道的拮抗剂。我们的拮抗剂衍生肽已被证明 增强吗啡镇痛作用，并对其具有一定的镇痛活性 自己的。我们的衍生化 haxapeptides 作为镇痛药和药物具有巨大的潜力 第一阶段的研究结果将为进一步开发奠定基础 用于慢性和急性疼痛的非成瘾性镇痛药。阶段的具体目标 II 是： (I) 设计有效衍生的六肽的非肽类似物 增强效力、功效和半衰期。进行计算实验 设计这些类似物。 (ii) 进行体外实验以研究结合 亲和力。 (iii) 对高亲和力化合物进行功能测定以确定 激动剂和拮抗剂活性。 (iv) 进行体内高实验 用于镇痛或伤害感受活性的亲和力激动剂和拮抗剂。 （五） 对最有效的激动剂和拮抗剂进行体内实验 确定他们在慢性疼痛模式下的行为。这些产生的数据 研究将为将该技术提升到一个水平提供重要信息 成熟度足以成功竞争商业资金，从而带来 临床使用的有效治疗剂。 拟议的商业应用： 根据该计划制备的伤害肽非肽类似物将被开发成 可用于治疗慢性疼痛和神经性疼痛的疗法。 为了这 一种使人衰弱的慢性损伤，目前没有合适的治疗方法。 市场 止痛药的市场价值超过 50 亿美元，并且正在迅速增长。 这 非肽激动剂的开发可能会为此添加有效的化合物 巨大的市场。