Bioactivity Of Neuropeptides

神经肽的生物活性

基本信息

项目摘要

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.
工作总结:最近开发的阿片样物质模拟物的药理学和生理学活性测定在体内使用小鼠在比较吗啡和使用一般以及特定的阿片拮抗剂,以评估其作用模式。抗伤害感受特征与使用豚鼠回肠和小鼠输精管测定系统的体外功能药理学数据平行,并反映了受体结合亲和力(有关肽与δ-和μ-阿片受体相互作用的详细信息,请参见先前的项目)。一系列新的含Dmt的吡嗪酮阿片样物质模拟化合物在体内具有特殊的活性,其中一种在i.c.v.给药后使用标准测试程序产生镇痛作用方面比吗啡强60至71倍,但这取决于测试测量的是脊髓还是脊髓上的作用;前者比后者更有效。特别地,化合物3-[4 ′-Dmt-氨基丁基]-6-(3 ′-Dmt-氨基丙基)-5-甲基-2(1H)吡嗪酮在所有测定系统中具有非常高的亲和力(Ki μ = 0.02 nM)、选择性(delta/mu = 1,520)和激动剂活性(GPI,IC 50 = 1.7 nM),对delta受体具有弱活性。该化合物主要通过使用mu-2受体亚型的脊髓抗伤害感受来产生脊髓抗伤害感受;然而,mu-1亚型在脊髓上占主导地位。南卡罗来纳注射产生CNS介导的抗伤害感受,提供了化合物通过胃肠道和脑中微毛细血管紧密连接中的膜屏障的证据。然而,一周后获得的耐受性相当于吗啡,这表明两种物质通过类似的机制作用于μ阿片受体。 另一类含Dmt的吡嗪酮化合物,3,6-双-[Dmt-NH-(CH2)n]-2(1H)-吡嗪酮化合物不仅表现出中枢(CNS)介导的镇痛作用,而且是口服生物可利用的阿片样物质模拟物。这些对称物质对μ-阿片受体表现出高亲和力(Ki = 0.04 - 0.12 nM),对GPI表现出强的血管紧张作用(IC 50 = 1.3 - 1.9 nM)。它们在体内通过i.c.v.给药产生的镇痛作用比吗啡强50 - 63倍,但在s.c.注射时只有大约一半的效力。或口服给药,其仍然比其他内源性阿片肽大几个数量级,并且重要的是,其未被糖基化、金刚烷、甘油三酯、卤素、抗体、生物素、大体积有机分子、C-末端羧基的酯化(在这些化合物中不存在)或Tyr或Dmt的酚羟基的O-酰化,也不需要将它们吸收到聚山梨酯包被的纳米颗粒上以诱导通过BBB的摄取。

项目成果

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LAWRENCE H LAZARUS其他文献

LAWRENCE H LAZARUS的其他文献

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{{ truncateString('LAWRENCE H LAZARUS', 18)}}的其他基金

MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES
阿片肽的分子动力学构象
  • 批准号:
    6106788
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
MOLECULAR DYNAMICS CONFORMATION OF OPIOID PEPTIDES
阿片肽的分子动力学构象
  • 批准号:
    6290083
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7007485
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bioactivity Of Opioidmimetic Substances
阿片类物质的生物活性
  • 批准号:
    7968153
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bioactivity Of Opioidmimetic Substances
阿片类物质的生物活性
  • 批准号:
    8149072
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
MOLECULAR BIOLOGY OF OPIOID MEMBRANE RECEPTORS
阿片类膜受体的分子生物学
  • 批准号:
    6106802
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7217694
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7328899
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7593970
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Molecular Dynamics Conformation Of Opioid Peptides
阿片肽的分子动力学构象
  • 批准号:
    7734503
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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