Bioactivity Of Opioidmimetic Substances

阿片类物质的生物活性

• 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
• 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' ,6' -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

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：通过与吗啡（μ-阿片受体激动剂）和deltorpin（δ-阿片受体激动剂）比较，在小鼠体内测定最近开发的阿片样物质的抗伤害感受和该活性的拮抗剂，以评估它们的作用模式。 抗伤害感受特征与体外功能药理学数据GPI（豚鼠回肠）和MVD（小鼠输精管）一致，并反映了阿片受体结合亲和力（有关化合物与δ-和μ-阿片受体相互作用的详细信息，请参见项目1）。一系列新型Dmt-Tic药理学药物或原型药物在体外和体内使用热板（脊髓上作用，中枢神经系统）和甩尾试验（脊髓作用）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，是口服生物可利用的阿片样物质。 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性，这表明多药耐药P-糖蛋白1参与了这一观察，由于这些阿片类似物在体外抑制Pg-1。 其他Dmt-Tic化合物，特别是MZ-2（专利申请中）可以防止对吗啡和烯丙基化内吗啡（见下文）的耐受性的形成，但相比之下，它可以作为双重拮抗剂来抑制δ-和μ-阿片活性。 此外，耐受性的消除发生在没有纳洛酮和纳洛酮的严重副作用的情况下。 对内吗啡肽-1和-2中含有Dmt代替Tyr的μ阿片激动剂的研究揭示了它们的作用模式的差异，这也有助于区分这些结构上相关的化合物。 虽然这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明显不同。 Dmt在体外和体内均使所有测得的活性参数提高了几个数量级。 两种内吗啡的N-烯丙基衍生物是有效的μ-阿片类拮抗剂，如小鼠脑室内给药所示：它们有效地抑制吗啡抗伤害作用，类似于纳洛酮。