SYSTEMICALLY ADMINISTERED DYNORPHINS

全身使用强啡肽

• 批准号: 2749175
• 负责人: EDUARDO R BUTELMAN
• 金额: $ 23.42万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-29 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749175
• 关键词: Macaca mulatta; acetamides; benzene; bradykinin; diuretics; drug interactions; dynorphins; fentanyl; hyperalgesia; naltrexone; opioid receptor; peptide analog; prostaglandin E; psychomotor function; psychopharmacology; respiratory pharmacology; self medication; sensory depression; urinalysis

The dynorphins comprise both endogenous opioid peptides such as dynorphin A 1-17 and fragments of dynorphin A, as well as peptide analogs based on the dynorphin structure. Dynorphin A has been proposed as the endogenous ligand for the K type of opioid receptor, and many of the dynorphins do show K-selective profiles of action. Most studies examining the in vivo effects of the dynorphins have examined the effects of the central (eg. intracerebroventricular or intrathecal) administration of dynorphins in rodents; the effect of systemic administration of these compounds in other species, and especially in primates, has not been well studied. Such studies are important since 1) clinically-useful drugs are ideally active following systemic administration and 2)rodents are probably not the best species for the preclinical evaluation of potential K-selective compounds since they have been shown to possess populations of K receptors that are quantitatively and qualitatively distinct from those found in primates. The dynorphins have emerged as a set of compounds especially deserving of such scrutiny since preliminary experiments indicate that systemic (iv) administration of dynorphin 1-13 and the recently-developed dynorphin analog E-2078 may produce analgesic effects without the dysphoric subjective effects that have impeded the clinical application of the alkaloid K agonists. The proposed experiments will follow up on this lead by examining in detail the agonist effects of a series of systemically-administered dynorphins in rhesus monkeys in assays of antinociception (warm-water tail-dip procedure and prostaglandin E2-induced hyperalgesia/allodynia), drug discrimination (monkeys trained to discriminate E-2078 from saline or the K agonist U69,593 from saline), food-reinforced operant responding (monkeys trained to respond under FR3O schedule of food reinforcement), gross behavior (observational rating scales of muscle relaxation and sedation), diuresis (volume of urination during three-hour test sessions) and reinforcement (substitution in monkeys trained to self-administer alfentanil). Any agonist effects will be evaluated for susceptibility to antagonism by the mu-selective opioid antagonist quadazocine, the K-selective antagonist nor-binaltorphimine, and, if warranted, the delta-selective antagonist naltrindole. The results of the these studies should reveal the degree to which prototypical members of the dynorphin family share a similar profile of agonist effects with potential for clinical application. In addition, these studies will provide information relevant to identifying the structural requirements for systemic dynorphin activity, which will inform the design and synthesis of new compounds. Finally, these studies will determine the role of K opioid receptors in mediating the effects of systemically-administered dynorphins.

强啡肽包括两种内源性阿片肽，如强啡肽 A 1-17和强啡肽A的片段，以及基于 强啡肽结构。强啡肽A被认为是内源性的 K型阿片受体的配体，许多强啡肽都有 显示动作的K选择配置文件。大多数研究都在体内检测 强啡肽的作用研究了中枢神经系统的作用(如。 脑室或鞘内注射强啡肽 啮齿动物；全身给药这些化合物的影响 其他物种，特别是灵长类动物，还没有得到很好的研究。 这样的研究很重要，因为1)临床上有用的药物是理想的 全身给药后很活跃，2)啮齿动物可能不是 K-选择素潜在临床前评价的最佳物种 化合物，因为它们已被证明具有K 与那些在数量和质量上不同的受体 在灵长类动物中发现。强啡肽以一系列化合物的形式出现 尤其值得这样仔细检查，因为初步实验 表明全身(Iv)给药强啡肽1-13和 新近开发的强啡肽类似物E-2078可产生镇痛作用 没有烦躁不安的主观影响，阻碍了临床 生物碱K激动剂的应用。拟议中的实验将 通过详细检查一种药物的激动剂效应来追踪这一线索 年恒河猴全身给药强啡肽系列 抗伤害性试验(温水浸尾试验和 前列腺素E_2引起的痛觉过敏/超敏)，药物辨别 (训练猴子区分E-2078和生理盐水或K激动剂 U69,593来自生理盐水)，食物强化操作物反应(训练猴子 在FR3O食品强化计划下做出反应)，粗俗行为 (肌肉松弛和镇静的观察性分级量表)，利尿 (三个小时测试期间的尿量)和加强 (被训练为自我给药阿芬太尼的猴子的代用品)。任何 激动剂的效果将通过以下方法评估对拮抗的敏感性 MU选择性阿片拮抗剂四唑辛，K选择性拮抗剂 Nor-binaltorphimine，如果有必要，还可以使用Delta选择性拮抗剂 那曲哚。这些研究的结果应该揭示出 强啡肽家族的哪些典型成员有类似的 具有临床应用潜力的激动剂作用概况。在……里面 此外，这些研究将提供与确定 全身强啡肽活动的结构要求，这将 通知新化合物的设计和合成。最后，这些研究 将确定K阿片受体在介导阿片受体效应中的作用 全身注射强啡肽。