Bioactivity Of Opioidmimetic Substances

阿片类物质的生物活性

• 批准号: 7328920
• 负责人: LAWRENCE H LAZARUS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7328920
• 关键词: Bioactivity; Opioidmimetic; Substances

Summary of Work: Antinociception and antagonists to this activity by recently developed opioidmimetic substances was determined in vivo in mice in comparison to morphine (mu-opioid receptor agonist) and deltorpin (delta agonist) to assess their mode of action. The antinociception profile paralleled that of the in vitro functional pharmacological data [GPI (guinea-pig ileum) and MVD (mouse vas deferens)] and reflected the opioid-receptor binding affinity (see, Project 1 for details on the interaction of compounds with delta- and mu-opioid receptors). A series of novel bis-Dmt-Tic-containing alkyl and Dmt-alkyl pyrazinone group as opioidmimetic compounds exhibited antagonism in vitro and in vivo using the hot-plate test which measures supraspinal effects (central nervous system). The control compounds, 3,6-bis-[Dmt-NH-(CH2)n]-2(1H)-pyrazinone compounds, in contrast exhibited central (CNS) mediated analgesia and wereorally bioavailable opioidmimetics. Interestingly, the N,N-dimethyl-Dmt-Tic-NH-adamantane and -tert-butyl derivatives inhibited tolerance to morphine in mice, which suggests that the multidrug resistance P-glycoprotein 1 was involved in this observation due to the inhibition in vitro of Pg-1 by these opioid analogues. Studies on the mu opioid agonists containing Dmt in lieu of Tyr in endomorphins-1 and -2 revealed differences in their mode of action that also serve to differential these stucturally related compounds. Whereas both compounds exhibited potent analgesia, their mode of action and degree of analgesia was significantly different. Dmt enhanced all measured parameters of activity by orders of magnitude both in vitro and in vivo. The N-allyl derivatives of both endomorphines were potent mu-opioid antagonists as demonstrated by intracerebroventricular administration in mice: they effectively inhibited morphine antinociception similar to naloxone.

研究人员在小鼠体内测定了最近开发的阿片样物质的抗痛觉作用和这种活性的拮抗剂，并与吗啡（阿片受体激动剂）和德尔托平（激动剂）进行了比较，以评估它们的作用方式。抗痛感谱与体外功能药理学数据[GPI（豚鼠回肠）和MVD（小鼠输精管）]相似，反映了阿片受体的结合亲和力（参见项目1，有关化合物与δ -和μ -阿片受体相互作用的详细信息）。用热板法测定椎管上作用（中枢神经系统），研究了一系列新型的含双dmt - tic烷基和dmt -烷基吡嗪酮类阿片类化合物在体外和体内表现出拮抗作用。对照化合物3,6-双-[dmt - nh2 -(CH2)n]-2(1H)-吡嗪酮化合物则表现出中枢（CNS）介导的镇痛作用，是口服的生物可利用的阿片类药物。有趣的是，N，N-二甲基- dmt - tic - nh -金刚烷和-叔丁基衍生物抑制了小鼠对吗啡的耐受性，这表明多药耐药p -糖蛋白1参与了这一观察，因为这些阿片类似物在体外抑制Pg-1。