Bioactivity Of Opioidmimetic Substances

阿片类物质的生物活性

基本信息

批准号：
7734512
负责人：
LAWRENCE H LAZARUS
金额：
$ 27.49万
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/7734512
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 Blood specimen Brain Bulimia Cavia Characteristics Chronic Clinical Computers Condition Data Development Dietary intake Disease Eating Disorders End Point Exhibits Food Future Gambling Hand Heroin Human Immune In Vitro Lead Legal patent Leptin Ligands Malignant Neoplasms Measures Mediating Medicine Minor Morphine Morphine Dependence 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 Population 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 United States Food and Drug Administration Vas deferens structure Video Games Weight Gain Withdrawal Symptom addiction alcohol abuse therapy alcohol craving analog base clinically significant craving drug craving fighting food craving ileum in vivo insight mouse model mu opioid receptors neural circuit neurobehavioral novel pleasure prevent psychologic receptor relating to nervous system response trait

项目摘要

Antinociception and antagonists to this activity by recently developed opioidmimetic substances was determined in comparison to morphine (mu-opioid receptor agonist) and deltorpin (delta-opioid agonist) to assess their mode of action using mice models. 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. In addition, MZ-2 decreased food intact in ob/ob mice and altered the levels of several key indicators of obesity in the clinical analyses of blood samples; the data portend an application of MZ-2 in fighting obesity in human populations. 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. N-allyl-Dmt-1endomorphin-1 and -2 derivatives were potent mu-opioid antagonists as demonstrated by intracerebroventricular administration in mice: they effectively inhibited morphine antinociception similar to naloxone. Both compounds effectively and completely eliminated withdrawal symptoms following either acute or chronic morphine addiction in mice, which differs from the detrimental effects by naloxone or naltrexone, a FDA approved drug in the treatment of alcoholism and addiction to dibilitating drugs, such as morhphine and heroin.

与吗啡（Mu-阿片受体激动剂）和Deltorpin（Delta-Opioid激动剂）相比，确定了最近开发的阿片类药物对这种活性的抗伤害感受和拮抗剂，以使用小鼠模型评估其作用方式。抗伤害感吸收曲线与体外功能药理学数据GPI（豚鼠）和MVD（小鼠VAS deferens）平行，并反映了阿片类药物受体受体结合亲和力（有关化合物与Delta-和Mu- opopie-opopiole Hosedor的相互作用的详细信息，请参见项目1。一系列新型的DMT-TIC药物塑料药物或原虫药物在体外表现出拮抗作用，并使用热板（脊柱上性效应，中枢神经系统）和尾脸 - 轻便测试（脊髓效应）表现出拮抗作用。对照化合物表现出中央（CNS）介导的镇痛作用，并且是口服可生物利用的阿片类动物。有趣的是，N，N-二甲基-DMT-DMT-TIC-NH-甲烷和-TERT叔丁基衍生物抑制了小鼠中吗啡的耐受性，这表明由于这些阿片类模拟的PG-1抑制作用，多药耐药P-糖蛋白1与这种观察有关。其他DMT-TIC化合物MZ-2，特别是（专利申请申请）可以防止形成对吗啡的耐受性，并且像烯丙基化的内态（Infra Vide）一样，但相比之下，它是双重拮抗剂，可以抑制delta-和Mu-Opobioid活性。此外，消除了耐受性，没有纳洛酮和纳曲酮的严重副作用。此外，在血液样本的临床分析中，MZ-2减少了OB/OB小鼠的食物完整，并改变了肥胖的几个关键指标的水平。该数据预示了MZ-2在人群中与肥胖作斗争的应用。对含有DMT代替Tyr的MU阿片类动力学家在内粒素-1和-2中代替Tyr的研究表明，其作用方式的差异也有助于这些相关的化合物差异。尽管两种化合物都表现出有效的镇痛作用，但它们的作用方式和镇痛程度显着差异。 DMT通过体外和体内通过数量级来增强所有测量活性参数。 N- Alyl-DMT-1端酚-1和-2衍生物是小鼠脑室内给药的有效的MU阿片类拮抗剂：它们有效抑制了类似于NALOXONE的吗啡抗伤害感受。两种化合物在小鼠中急性或慢性吗啡成瘾后都有效地消除了戒断症状，这与纳洛酮或纳曲酮的有害作用不同，纳洛酮或纳曲酮的有害作用是FDA批准的药物，用于治疗酒精中毒和成瘾以二脂药物（例如莫芬肾和海洛因）。