Bioactivity Of Opioidmimetic Substances

阿片类物质的生物活性

• 批准号: 7968153
• 负责人: LAWRENCE H LAZARUS
• 金额: $ 27.58万
• 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/7968153
• 关键词: Absence of pain sensation; Ache; Acute; Adamantane; Addictive Behavior; Adult; Adverse effects; Affect; Affinity; Agonist; Alcoholism; Alcohols; Amaze; Analgesics; Anorexia Nervosa; Appearance; Bioavailable; Biological Assay; Blood - brain barrier anatomy; Blood specimen; Bone Density; Brain; Bulimia; Cavia; Characteristics; Child; Chronic; Clinical; Computers; Data; Development; Dietary intake; Disease; Eating; Eating Disorders; Exhibits; FDA approved; Food; Future; GTP-Binding Proteins; Gambling; Hand; Health; Human; Immune; In Vitro; Lead; Legal patent; Leptin; Ligands; Malignant Neoplasms; Mediating; Medicine; Minor; Morphine; Morphine Dependence; Multi-Drug Resistance; Mus; N,N-dimethyl-2' ,6' -dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Neuraxis; Obesity; Opioid; Opioid Peptide; Opioid Receptor; Opioid Receptor Binding; Overweight; P-Glycoprotein; Pain; Pathogenesis; Pathway interactions; Perception; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Play; Population; Post-Traumatic Stress Disorders; Predisposition; Preparation; Property; Rewards; Risk; Role; Scientist; Series; Smoking; Spinal; Staging; Stress; Symptoms; System; Tail; Television; Testing; Therapeutic; Trauma; Twin Multiple Birth; Vas deferens structure; Video Games; Weight Gain; Withdrawal Symptom; addiction; alcohol abuse therapy; alcohol craving; alcoholism therapy; analog; base; clinically significant; craving; drug craving; fighting; food craving; ileum; in vivo; insight; meetings; mouse model; mu opioid receptors; neural circuit; neurobehavioral; novel; peptide structure; pleasure; prevent; psychologic; receptor; relating to nervous system; response; trait

Antinociception (analgesia) 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 in addition to the assessment of G-protein interaction using the GTP-gamma-S assays, which represent an in vitro analysis of the pharmacological preparations. 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, N,N-dimethyl-Dmt-Tic-NH-adamantane and H-Dmt-Tic-NH--tert-butyl derivatives inhibited tolerance to morphine in mice, which suggests that the multidrug resistance P-glycoprotein 1 was involved due to their inhibition in vitro of Pg-1. Other Dmt-Tic compounds, such as MZ-2, in particular (patent application pending) prevents the formation of tolerance to morphine like the N-allyl-Dmtendomorphin analogues, which are neutral opioid antagonists following morphine or alcohol treatment. Furthermore, the elimination of tolerance occurred without the severe side-effects seen with both naloxone and naltrexone, a FDA approved drug for the treatment of alcoholism. N-allyl-Dmtendomorphin-1 and -2 derivatives were highly potent mu-opioid antagonists as demonstrated by intracerebroventricular administration in mice: they effectively inhibited morphine antinociception similar to naloxone, a standard mu-opioid receptor antagonist. Both compounds effectively and completely eliminated withdrawal symptoms following either acute or chronic morphine addiction in mice. In addition, MZ-2 decreased food intake in ob/ob mice, altered the levels of several key indicators of obesity in the clinical analyses of blood samples and elevated bone mineral density; the data portend an application of MZ-2 in fighting obesity in human populations.

通过与吗啡（阿片受体激动剂）和德尔托平（阿片受体激动剂）进行比较，确定了最近开发的阿片样物质的抗痛感（镇痛）和拮抗剂，并利用小鼠模型评估了它们的作用模式。抗痛感谱与体外功能药理学数据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，以及使用gtp - γ - s测定g蛋白相互作用的评估，这代表了药物制剂的体外分析。通过热板实验（脊柱上作用、中枢神经系统作用）和甩尾实验（脊柱作用），研究了一系列新型Dmt-Tic药效药物或原药在体外和体内表现出拮抗作用。对照化合物表现出中枢（CNS）介导的镇痛作用，是口服的生物可利用的类阿片药物。有趣的是，N，N-二甲基- dmt - tic - nh -金刚烷和H-Dmt-Tic-NH-叔丁基衍生物抑制了小鼠对吗啡的耐受性，这表明由于它们在体外抑制Pg-1，多药耐药p -糖蛋白1参与其中。其他Dmt-Tic化合物，如MZ-2，特别是（专利申请中）阻止像n -烯丙基- dmtendomorphin类似物一样对吗啡产生耐受性，这是吗啡或酒精治疗后的中性阿片类拮抗剂。此外，耐受性的消除没有出现纳洛酮和纳曲酮的严重副作用，纳曲酮是FDA批准的治疗酒精中毒的药物。n-烯丙基- dmtendomorphin -1和-2衍生物是高效的mu-阿片受体拮抗剂，经小鼠脑室内给药证实：它们有效抑制吗啡抗痛感，类似于纳洛酮（一种标准的mu-阿片受体拮抗剂）。这两种化合物都能有效地完全消除小鼠急性或慢性吗啡成瘾后的戒断症状。此外，MZ-2减少了ob/ob小鼠的食物摄入量，改变了血液样本临床分析中肥胖的几个关键指标的水平，并提高了骨密度；这些数据预示着MZ-2在对抗人类肥胖方面的应用。