Bioactivity Of Opioidmimetic Substances

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，确定最近开发的阿片样物质的抗伤害感受（镇痛）和该活性的拮抗剂，以使用小鼠模型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，并反映了阿片样物质受体结合亲和力，以及使用GTP-γ-S测定法评估G-蛋白相互作用，这代表了药理学制剂的体外分析。 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H-Dmt-Tic-NH-叔丁基衍生物抑制小鼠对吗啡的耐受性，这表明由于它们在体外抑制Pg-1，因此涉及多药耐药P-糖蛋白1。 其他Dmt-Tic化合物，例如MZ-2，特别是（专利申请待审）防止形成对吗啡的耐受性，如N-烯丙基-Dmtendomorphin类似物，其是吗啡或酒精治疗后的中性阿片样物质拮抗剂。 此外，耐受性的消除发生在没有纳洛酮和纳洛酮（FDA批准的用于治疗酒精中毒的药物）的严重副作用的情况下。N-烯丙基-Dmtendomorphin-1和-2衍生物是高度有效的μ-阿片类拮抗剂，如通过小鼠脑室内给药所证明的：它们有效地抑制吗啡抗伤害感受，类似于纳洛酮，一种标准的μ-阿片类受体拮抗剂。 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，并提高了骨矿物质密度;这些数据预示着MZ-2在人类肥胖症中的应用。

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.