Bioactivity Of Opioidmimetic Substances

以吗啡(Mu-阿片受体激动剂)和德尔托品(Delta-阿片激动剂)为对照，用小鼠模型研究了新近开发的类阿片类物质的镇痛和拮抗剂的作用模式。抗伤害性数据与体外功能药理数据GPI(豚鼠回肠)和MVD(小鼠输精管)相似，反映了阿片受体与阿片受体的结合亲和力，并用GTP-伽马-S法评估G蛋白相互作用，这代表了药理制剂的体外分析。一系列新型DMT-Tic药物或原药物在体内外表现出拮抗作用，采用热板法(脊髓上效应)和甩尾试验(脊髓效应)。对照化合物具有中枢(CNS)介导的镇痛作用，是口服生物利用型阿片类药物。有趣的是，N，N-二甲基-DMT-Tic-NH-金刚烷和H-DMT-Tic-NH-叔丁基衍生物抑制小鼠对吗啡的耐受性，这表明它们在体外对PG-1的抑制作用与多药耐药P-糖蛋白1有关。其他DMT-Tic化合物，如MZ-2，特别是(专利申请正在申请中)防止形成对吗啡的耐受性，如N-烯丙基-Dmtendomin类似物，它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-D肌腱吗啡-1和-2衍生物是一种高效的Mu阿片受体拮抗剂，小鼠脑室给药证明：它们能有效地抑制吗啡的抗伤害作用，与标准Mu阿片受体拮抗剂纳洛酮相似。这两种化合物都有效地完全消除了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，改变了临床血样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在人类群体中对抗肥胖的应用。

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.