Bioactivity Of Opioidmimetic Substances

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，特别是MZ-2（正在申请专利），可防止形成对吗啡的耐受性。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。MZ-2有效地完全消除小鼠急性或慢性吗啡成瘾后的戒断症状和耐受性。此外，MZ-2降低了ob/ob小鼠和饮食性肥胖小鼠模型的食物摄入量，改变了血液样本临床分析中肥胖的几个关键指标的水平。重要的是，MZ-2提高了体内骨矿物质密度，体外培养细胞中骨钙素的形成增加了约30%，而纳曲酮的有效性仅为17%；吗啡使这种现象减少了17%。这些数据提示MZ-2在对抗人类肥胖和骨质疏松症方面的潜在应用。

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. 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. MZ-2 effectively and completely eliminated withdrawal symptoms and tolerance following either acute or chronic morphine addiction in mice. In addition, MZ-2 decreased food intake in ob/ob mice and diet-induced obesity mice models, altered the levels of several key indicators of obesity in the clinical analyses of blood samples. Importantly, MZ-2 elevated bone mineral density in vivo and increased the osteocalcin formation in cell cultures in vitro about 30%, whereas naltrexone was only about 17% effective; morphine decreased this phenomenon by 17%. These data suggestion the potential application of MZ-2 in fighting bother obesity and osteoporosis in human populations.