Metabolically programmed polyamine analogue antidiarrheals.
Metabolically programmed polyamine analogue antidiarrheals.
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代谢程序化的多胺类似物止泻药。
DOI：
10.1021/jm950827h
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Gao,F
中科院分区：
文献类型：
--
作者：
Bergeron,RJ;Yao,GW;Yao,H;Weimar,WR;Sninsky,CA;Raisler,B;Feng,Y;Wu,Q;Gao,F
报道了一类基于四胺药效团的新型抗真菌药物的设计、合成和测试。虽然N，N14-二乙基高精胺（DEHSPM）（5 mg/kg）可完全预防啮齿类动物的腹泻，但组织分布研究表明，DEHSPM的主要代谢产物高精胺（HSPM）在组织中蓄积并持续较长时间。这种积累是二巯基丙烯酰胺慢性毒性的主要原因。因此，一个主要的目标是开发一种代谢不稳定的类似物DEHSPM保留所需的生物学特性的母体药物。将易受进一步代谢转化的羟基引入到外部氨基丁基片段中，提供N1，N14-二乙基-（3R），（12 R）-二羟基高精胺[（HO）2DEHSPM]。分子模型预测（HO）2DEHSPM的多胺转运活性与DEHSPM基本相同。（HO）2DEHSPM对L1210细胞的IC_（50）、对NMDA受体的影响、对L1210天然多胺库的影响等生物学特性的实验测定值与DEHSPM一致。然而，最重要的是，在长期使用（HO）2DEHSPM的小鼠组织中没有双去乙基代谢物的蓄积，并且（HO）2DEHSPM的毒性比DEHSPM低3倍。最后，（HO）2DEHSPM完全防止腹泻蓖麻油治疗的大鼠模型在5毫克/公斤的剂量，正如DEHSPM。
The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. WhileN,N14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providingN1,N14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)2DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)2DEHSPM would have aKifor polyamine transport essentially identical with that of DEHSPM. The experimentally measuredKiand also the observed values of other biological properties of (HO)2DEHSPM were in fact identical with those of DEHSPM, including IC50against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there wasno accumulationof the dideethylated metabolite in tissues from mice treated chronically with (HO)2DEHSPM, and (HO)2DEHSPM was3-foldless toxic than DEHSPM. Finally, (HO)2DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.