Development of Neurotensin-based Analgesics

神经降压素镇痛药的开发

• 批准号: 7157100
• 负责人: THOMAS A DIX
• 金额: $ 16.39万
• 依托单位: ARGOLYN BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-08 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7157100
• 关键词: analgesia; behavior test; bioengineering /biomedical engineering; blood chemistry; chemical stability; chronic pain; dosage forms; formaldehyde; laboratory rat; neuropathology; neuropeptide receptor; neurotensin; neurotransmitter antagonist; peptide chemical synthesis; protein isoforms; protein structure function; receptor binding; therapy design /development

DESCRIPTION (provided by applicant): Project Summary/Abstract: Chronic, neuropathic pain is 1 of the most important unmet medical needs in the United States, affecting tens to hundreds of millions of people nationwide at some time during their lives. Novel therapeutic approaches are desperately needed. The brain peptides neurotensin (NT) and its fully active derivative NT[8-13] have been shown to exhibit considerable, long-term analgesic activity, however the compounds are unable to be delivered across the blood brain barrier. In previous efforts, we have engineered a compound, ABS201, that possesses significant antipsychotic potential when orally administered; recently, we have demonstrated using an appropriate rat model of neuropathic pain that it also has dramatic analgesic activity. These activities are mediated through the compound's activity as an agonist of neurotensin receptor-(NTR-1) and NTR-2, respectively. While ABS201 has considerable promise for development as an analgesic, we hypothesize that further rational design will enable identification of a derivative in which NTR-2/NTR-1 receptor selectivity can be increased such that the antipsychotic activity is minimized or eliminated. 3 Specific Aims will be completed to address the hypothesis. In Specific Aim 1, a set of 10 derivatives of ABS 201 will be synthesized that are designed to improve selectivity of the compound for NTR-2 over NTR-1 and thus retaining analgesic activity. These compounds (as well as ABS201) will be evaluated in Specific Aim 2 for analgesic activity in 3 rat models, the tail flick, hotplate and formalin assays for chronic pain. Both IP and oral dosing will be performed for all compounds. In Specific Aim 3, other potential discriminators, including NTR-2 and NTR-1 binding, serum stability and functional agonism will be evaluated. From the results of these studies, a lead will be identified for advancement into Phase 2 of this project, which will include further evaluation of the compound's efficacy, potential for toxicity and pharmacokinetic characterization appropriate for submission of an IND. Specific Aim 1 will be completed at Argolyn Bioscience while Specific Aims 2 and 3 will be completed under a subcontract at the Medical University of South Carolina. Project Narrative: Chronic, neuropathic pain is 1 of the most important unmet medical needs. An orally active derivative of the brain peptide neurotensin has been identified that exhibits potent analgesic activity in rats equivalent to morphine but with a unique mechanism of activity. This compound has the potential for development as a novel therapeutic agent for chronic pain.

描述（由申请人提供）：项目摘要/摘要：慢性，神经性疼痛是美国最重要的未满足医疗需求之一，一生中的某个时候影响了全国数千万人。迫切需要新颖的治疗方法。脑肽神经素（NT）及其完全活跃的衍生化NT [8-13]已显示出相当大的长期镇痛活性，但是这些化合物无法在血脑屏障中递送。在先前的努力中，我们设计了一种ABS201的化合物，该化合物在口服时具有巨大的抗精神病药。最近，我们已经使用适当的神经性疼痛大鼠模型证明了它也具有巨大的镇痛活性。这些活性分别通过该化合物的活性作为神经素受体（NTR-1）和NTR-2的激动剂进行介导。尽管ABS201作为一种镇痛作用具有相当大的发展，但我们假设进一步的合理设计将鉴定出可以提高NTR-2/NTR-1受体选择性的衍生物，从而可以提高抗精神病毒活性最小化或消除。 3个具体目标将完成以解决该假设。在特定的目标1中，将合成一组10个ABS 201的衍生物，旨在提高NTR-2对NTR-1的选择性，从而保持镇痛活性。这些化合物（以及ABS201）将在特定的目标2中评估3种大鼠模型中的镇痛活性，尾部轻弹，热板和福尔马林测定法，用于慢性疼痛。所有化合物都将执行IP和口服给药。在特定的目标3中，还将评估其他潜在歧视因子，包括NTR-2和NTR-1结合，血清稳定性和功能激动剂。从这些研究的结果来看，将确定铅的铅，以发展到该项目的第2阶段，其中包括对化合物的功效，毒性的潜在和药代动力学表征的进一步评估，适合于提交IND。特定目标1将在Argolyn Bioscience完成，而特定目标2和3将根据南卡罗来纳州医科大学的分包合同完成。项目叙述：慢性，神经性疼痛是最重要的未满足医疗需求之一。已经鉴定出一种脑肽神经素的口服衍生物，它在相当于吗啡的大鼠中表现出有效的镇痛活性，但具有独特的活性机制。该化合物具有作为慢性疼痛的新型治疗剂的发育潜力。