Bioactivity Of Neuropeptides

神经肽的生物活性

• 批准号: 6838631
• 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/6838631
• 关键词: biomimetics; blood brain barrier; endogenous opioid; inhibitor /antagonist; laboratory mouse; morphine; neuropeptides; nociceptin; peptide analog; pharmacokinetics; pyrazines; receptor binding

Summary of Work: The pharmacological and physiological activity of recently developed opioid mimetic substances were determined in vivo using mice in comparion to morphine and using general as well as specific opiate antagonists to assess their mode of action. The antinociception profile paralled that of the in vitro functional pharmacological data using guinea-pig ileum and mouse vas deferens assay systems, and reflected the receptor binding affinity (see previous projects for details on the interaction of peptides with delta- and mu-opioid receptors). A series of novel Dmt-containing pyrazinone opioid mimetic compounds had exceptional activity in vivo, one of which was 60- to 71-fold more potent than morphine in generating analgesia using standard testing procedures after i.c.v. administration, but depending on whether the test measured spinal or supraspinal effects; the former being more potent than the latter. In particular, the compound 3-[4'-Dmt-aminobutyl)-6-(3'-Dmt-aminopropyl0-5-methyl-2(1H)pyrazinone had very high affinity (Ki mu = 0.02 nM), selectivity (delta/mu = 1,520) and agonist activity (GPI, IC50 = 1.7 nM) with weak activity toward the delta receptor in all assay systems. This compound acted to produce spinal antinociception primarily through spinal antinociception using the mu-2 receptor subtype; however, the mu-1 subtype dominates supraspinally. The s.c. injection produced CNS-mediated antinociception, providing evidence the compound passed through memrane barriers in both the gastrointestinal tract and in the microcapillary tight junctions in the brain. However, a tolerance was obtained after a week that was equivalent to morphine that suggests that both substances act through similar mechanisms at mu-opioid receptors. Another class of Dmt-containing pyrazinone compounds, the 3,6-bis-[Dmt-NH-(CH2)n]-2(1H)-pyrazinone compounds not only exhibited central (CNS) mediated analgesia, but also were orally bioavailable opioid mimetics. These symmetric substances displayed high affinity for mu-opioid receptors (Ki = 0.04-0.12 nM) and potent angonism on GPI (IC50 = 1.3-1.9 nM). They produced analgesia in vivo by i.c.v. administration that was 50- to 63-fold more potent than morphine, but only about half as potent when injected s.c. or administered orally, which is still orders of magnitude greater than other endogenous opioid peptides and, importantly, were unmodified by glycosylation, adamantane, triglycerides, halogens, antibody, biotin, bulky organic molecules, esterification of a C-terminal carboxyl group (of which none exist in these compounds) or O-acylation of the phenolic hydroxyal group of Tyr or Dmt, nor was it necessary to absorb them onto polysorbate coated nanoparticles to induced uptake through the BBB.

工作摘要：与吗啡相比，使用小鼠以及使用一般的鸦片拮抗剂来评估其作用方式，使用小鼠在体内确定了最近开发的阿片类模拟物质的药理和生理活性。抗伤害感受的曲线与豚鼠和小鼠VAS递延测定系统的体外功能药理学数据相吻合，并反映了受体结合亲和力（有关肽与Delta-和Mu-Apopiead受体的相互作用的详细信息，请参见先前的项目）。一系列新型含DMT的吡唑酮阿片类模拟化合物在体内具有出色的活性，其中一种在I.C.V.后使用标准测试程序产生镇痛时，在产生镇痛时，其有效性比吗啡高60至71倍。给药，但取决于测试是测量的脊柱还是脊柱上性作用；前者比后者更强大。特别是，化合物3- [4'-DMT-氨基丁基）-6-（3'-DMT-氨基丙基0-5-5-甲基-2（1H）吡嗪酮具有很高的亲和力（Ki Mu = 0.02 nm），选择性（delta/mu = 1,520）和agonist Active（gpi，IC50 = 1.7 nm）该化合物的作用是通过使用MU-2受体亚型来产生脊柱的抗伤害感，而MU-2受体亚型则占主导地位一周后，获得了耐受性，这表明两种物质都通过Mu-Apioid受体的相似机制起作用。 另一类含DMT的吡嗪酮化合物，3,6-双[DMT-NH-（CH2）N] -2（1H）-2（1H） - 吡嗪酮化合物，不仅表现出中心（CNS）介导的镇痛药，而且还表现出口服可生物可利用的opoibioid Mimimetics。这些对称物质显示出对Mu-阿片受体的高亲和力（KI = 0.04-0.12 nm）和GPI上的有效的Angonism（IC50 = 1.3-1.9 nm）。他们由I.C.V.在体内产生镇痛。给药比吗啡高50至63倍，但在注射S.C时只有大约一半的效力。或口服，它仍然比其他内源性阿片类肽要大的数量级，而且重要的是，通过糖基化，阿甘坦，甘油三酸酯，甘油三酸酯，卤素，抗体，抗体，生物素，笨重的有机分子，这些c-termalnical carboxyl coberation of tyrox of tyrrox of tyrrox of tyrrox of tyrros tyrros tyrros tyrros androsy therrosy tyrro tyrros and o physy of tyrrose tyrrose tyrro的酯（OO）均未通过糖基化，阿甘坦烷，甘油三酸酯，卤素，抗体，抗体，生物素分子。或DMT，也不需要将它们吸收到涂层的纳米颗粒上，以引起通过BBB的摄取。