In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species.
In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species.
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MPP 类似物和相关带电物质的大鼠体内脑内微透析研究。
DOI：
10.1021/jm00170a029
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发表时间：
1990
影响因子：
7.3
通讯作者：
CastagnoliJr,N
中科院分区：
文献类型：
--
作者：
Rollema,H;Johnson,EA;Booth,RG;Caldera,P;Lampen,P;Youngster,SK;Trevor,AJ;Naiman,N;CastagnoliJr,N
用清醒大鼠的胃内微透析法检测45种MPTP和MPP+类似物及相关化合物的体内多巴胺能神经毒性。尽管没有一种化合物的毒性比MPP+更强，但MPP+样毒性在多种结构类型中都有观察到，其对DA释放和乳酸形成的不可逆作用证明了这一点。可以推导出以下整体结构-毒性关系：(1)只有永久带电的化合物表现出神经毒性作用；(2)除氨基外，亲水性取代基消除毒性；(3)亲脂基团增强了活性，但氮原子周围空间体积的增加倾向于降低活性；(4)非芳香族季系（MPTP的甲氧基化合物、胍衍生物）毒性较弱；(5)某些双环和三环系统，包括潜在内源性mptp样化合物的推定代谢物，毒性较弱。DA本身灌注后没有毒性作用，证实MPTP多巴胺能神经毒性不可能是由MPP+诱导的DA释放介导的。除了一些有趣的例外，这些体内数据与这些化合物的神经末梢摄取特性和对线粒体呼吸的抑制作用的体外数据相当相关。
The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP+-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived:(1) only permanently charged compounds showed neurotoxic effects;(2) with the exception of amino groups, hydrophilic substituents abolished toxicity;(3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity;(4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi-and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP+-induced release of DA. With some interesting exceptions, these in vivo data correlatereasonably well with in vitro data on the nerve terminal uptake propertiesand the inhibitory effects on mitochondrial respiration of these compounds.