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的医疗需求之一，影响着全国数千万至数亿人的生活。迫切需要新的治疗方法。脑肽神经降压素（NT）及其完全活性衍生物NT[8-13]已显示出相当大的长期镇痛活性，然而，这些化合物不能穿过血脑屏障递送。在以前的努力中，我们已经设计了一种化合物，ABS 201，口服给药时具有显着的抗精神病潜力;最近，我们已经证明使用适当的神经性疼痛大鼠模型，它也具有显着的镇痛活性。这些活性分别通过化合物作为神经降压素受体（NTR-1）和NTR-2的激动剂的活性介导。虽然ABS 201作为镇痛药有相当大的发展前景，我们假设，进一步的合理设计将能够识别的衍生物，其中NTR-2/NTR-1受体的选择性可以增加，使抗精神病活性最小化或消除。将完成3个具体目标以解决假设。在具体目标1中，将合成ABS 201的一组10种衍生物，其设计用于改善化合物对NTR-2的选择性超过NTR-1，从而保留镇痛活性。这些化合物（以及ABS 201）将在3种大鼠模型中的特异性目标2中评价镇痛活性，以及慢性疼痛的甩尾、热板和福尔马林试验。将对所有化合物进行IP和口服给药。在特定目标3中，将评价其他潜在鉴别剂，包括NTR-2和NTR-1结合、血清稳定性和功能激动。根据这些研究的结果，将确定进入该项目2期的先导药物，其中将包括进一步评价该化合物的疗效、潜在毒性和适用于提交IND的药代动力学表征。具体目标1将在Argolyn Bioscience完成，而具体目标2和3将在南卡罗来纳州医科大学的研究中心完成。项目叙述：慢性神经性疼痛是最重要的未满足的医疗需求之一。已经鉴定了脑肽神经降压素的口服活性衍生物，其在大鼠中表现出与吗啡相当的有效镇痛活性，但具有独特的活性机制。该化合物具有开发为慢性疼痛的新型治疗剂的潜力。