Bioactivity Of Opioidmimetic Substances

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，如MZ-2，特别是（专利申请待审）防止对吗啡耐受性的形成。 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。MZ-2能有效地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减少了ob/ob小鼠和饮食诱导的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在体内提高了骨密度，在体外细胞培养中增加了约30%的骨钙素形成，而纳洛酮仅有效约17%;吗啡降低了17%。 这些数据表明MZ-2在对抗人类肥胖和骨质疏松症中的潜在应用。

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.