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类物质的镇痛（镇痛）和拮抗剂，以使用小鼠模型评估其作用模式。 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）的数据相似，除了使用 GTP-gamma-S 测定（代表药理制剂的体外分析）评估 G 蛋白相互作用之外，还反映了阿片受体结合亲和力。 一系列新型 Dmt-Tic 药效基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H-Dmt-Tic-NH-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由于它们在体外抑制Pg-1而参与其中。 其他 Dmt-Tic 化合物，例如 MZ-2，特别是（正在申请专利）可以防止吗啡耐受的形成，如 N-烯丙基-Dmtendomorphin 类似物，它们是吗啡或酒精治疗后的中性阿片拮抗剂。 此外，耐受性的消除没有出现纳洛酮和纳曲酮（FDA 批准的治疗酒精中毒的药物）所出现的严重副作用。 N-烯丙基-Dmtendomorphin-1 和 -2 衍生物是高效的 mu-阿片拮抗剂，如小鼠脑室内给药所证明的那样：它们有效地抑制吗啡镇痛，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且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 在对抗人类肥胖方面的应用。

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.