Bioactivity Of Opioidmimetic Substances

阿片类物质的生物活性

基本信息

批准号：
7593979
负责人：
LAWRENCE H LAZARUS
金额：
$ 29.75万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
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/7593979
关键词：
Absence of pain sensation Ache Acute Adamantane Addictive Behavior Adverse effects Affect Affinity Agonist Alcohol dependence Alcoholism Alcohols Amaze Analgesics Anorexia Nervosa Appearance Bioavailable Blood - brain barrier anatomy Brain Bulimia Cavia Characteristics Chronic Computers Condition Data Development Dietary intake Disease Eating Disorders End Point Exhibits Food Future Gambling Hand Human Immune In Vitro Lead Legal patent Ligands Malignant Neoplasms Measures Mediating Medicine Minor Morphine Multi-Drug Resistance Mus N,N-dimethyl-2&apos ,6&apos -dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid N-terminal Naloxone Naltrexone Narcotic Antagonists Narcotics Neuraxis Obesity Opioid Opioid Peptide Opioid Receptor Opioid Receptor Binding P-Glycoprotein Pain Pathogenesis Pathway interactions Perception Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Post-Traumatic Stress Disorders Predisposition Property Rewards Risk Role playing therapy Scientist Series Smoking Spinal Staging Stress Structure Symptoms System Tail Television Testing Therapeutic Today Trauma Twin Multiple Birth Tyrosine Vas deferens structure Video Games Weight Gain Work addiction alcohol craving analog base clinically significant craving drug craving food craving ileum in vivo insight mu opioid receptors neural circuit neurobehavioral novel pleasure prevent psychologic receptor relating to nervous system response trait

项目摘要

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-opioid 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 Dmt-Tic pharmacophoric drugs or protodrugs exhibited antagonism in vitro and in vivo using the hot-plate (supraspinal effects, the central nervous system) and tail-flick test (spinal effects). The control compounds exhibited central (CNS) mediated analgesia and were orally 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. Other Dmt-Tic compounds, MZ-2, in particular (patent application pending) prevents the formation of tolerance to morphine and like the allylated endomorphines (infra vide), but in contrast act as dual antagonists to inhibit both delta- and mu-opioid activities. Furthermore, the elimination of tolerance occurred without the severe side-effects seen with both naloxone and naltrexone. 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.

工作总结：与吗啡（μ-阿片受体激动剂）和 deltorpin（δ-阿片受体激动剂）相比，在小鼠体内测定了最近开发的阿片类物质的镇痛作用和该活性的拮抗剂，以评估其作用方式。镇痛特性与体外功能性药理学数据 GPI（豚鼠回肠）和 MVD（小鼠输精管）相似，并反映了阿片受体结合亲和力（有关化合物与 δ- 和 δ- 相互作用的详细信息，请参见项目 1） mu-阿片受体）。一系列新型 Dmt-Tic 药效团药物或原药在体外和体内利用热板（脊髓上效应，中枢神经系统）和甩尾试验（脊髓效应）表现出拮抗作用。对照化合物表现出中枢（CNS）介导的镇痛作用并且是口服生物可利用的阿片模拟物。有趣的是，N,N-二甲基-Dmt-Tic-NH-金刚烷和叔丁基衍生物抑制小鼠对吗啡的耐受，这表明多药耐药性P-糖蛋白1由于体外抑制作用而参与了这一观察结果这些阿片类似物对 Pg-1 的影响。其他 Dmt-Tic 化合物，特别是 MZ-2（正在申请专利）可防止形成对吗啡和烯丙基化内吗啡（见下文）的耐受性，但相反，可作为双重拮抗剂抑制 delta-和 mu-阿片类药物活动。此外，耐受性的消除没有出现纳洛酮和纳曲酮所见的严重副作用。对内吗啡肽-1 和 -2 中含有 Dmt 代替 Tyr 的 mu 阿片受体激动剂的研究揭示了它们作用模式的差异，这也有助于区分这些结构相关的化合物。尽管两种化合物均表现出有效的镇痛作用，但它们的作用方式和镇痛程度却显着不同。 Dmt 在体外和体内均将所有测量的活性参数提高了几个数量级。小鼠脑室内给药证明，两种内吗啡的 N-烯丙基衍生物都是有效的 mu-阿片类拮抗剂：它们能有效抑制吗啡的镇痛作用，类似于纳洛酮。