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Bioactivity Of Opioidmimetic Substances

Bioactivity Of Opioidmimetic Substances
阿片类物质的生物活性
批准号:
8149072
负责人:
LAWRENCE H LAZARUS
金额:
$29.49万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:

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中文摘要
翻译
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。
英文摘要
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.
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