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.

拟议项目的目的是为慢性开发一种非副本的镇痛药 和急性疼痛。 迫切需要有效治疗慢性神经性疗法 疼痛，糖尿病的相对常见并发症。作为糖尿病神经病 进展，神经性疼痛变得越来越难以治疗 目前可用的镇痛药，例如抗抑郁药和阿片类药物。吗啡 并且它的类似物通常是规定的，尽管它们具有副作用，但 因为目前尚无良好的镇痛药。新确定 Nocteptin及其在动物研究中的镇痛活性提供了潜力 缓解慢性和神经性疼痛的目标。因为nocteptin 拮抗剂不通过阿片受体，成瘾和阿片类药物作用 副作用可能不是问题。但是，由于其大小（17个氨基酸） 和肽性的性质，Nocceptin不会使其成为治疗剂。 将需要一个小的非肽类似物才能将任何化合物商业化。 在第一阶段的研究中，我们能够识别一组小衍生化 与人OL I受体具有高结合亲和力的十六进制肽。此外， 我们能够鉴定出具有功能活性的有效类似物 几乎是一个完整的拮抗剂的全部激动剂，至少有效性十倍 比报道的拮抗剂。我们的拮抗剂衍生肽已显示 增强吗啡镇痛，并在其上具有一些镇痛活性 自己的。我们衍生化的haxapeptides具有止痛药的潜力很大， 第一阶段的发现将构成进一步发展的基础 无成瘾的止痛药可用于慢性和急性疼痛。具体目标 II是：（i）设计有效衍生化的十六进肽的非肽类似物 提高效力，功效和半衰期。进行计算实验 设计这些类似物。 （ii）在体外实验进行研究 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）在高中进行体内实验 亲和力激动剂和对镇痛或伤害性活性的拮抗剂。 （v） 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中的行为。这些生成的数据 研究将提供重要的信息，以将该技术提高到一个水平 成熟的地方可以成功竞争商业资金来带来 有效的临床用途治疗剂。 拟议的商业应用： 根据该程序制备的NociTeptin的非肽类似物将发展为 可用于治疗慢性和神经性疼痛的治疗剂。 为了这 令人衰弱的慢性损伤类型，目前尚无合适的治疗方法。 市场 镇痛药的机会超过50亿美元，并且正在迅速增长。 这 开发非肽激动剂可能会为此增加有效的化合物 巨大的市场。