Characterization of a series of 3-amino-2-phenylpropene derivatives as novel bovine chromaffin vesicular monoamine transporter inhibitors.
Characterization of a series of 3-amino-2-phenylpropene derivatives as novel bovine chromaffin vesicular monoamine transporter inhibitors.
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DOI：
10.1021/jm030004p
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发表时间：
2003-05
影响因子：
7.3
通讯作者：
R. P. Perera;D. S. Wimalasena;K. Wimalasena
中科院分区：
文献类型：
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作者：
R. P. Perera;D. S. Wimalasena;K. Wimalasena
合成了一系列3-氨基-2-苯基丙烯（APP）衍生物，并对其进行了表征，它们是牛染色质颗粒膜单胺转运体（bVMAT）的新型竞争性抑制剂，其K(i)值在微米范围内。虽然这些抑制剂在结构上与bVMAT底物酪胺相似，但它们都没有被可测量地转运到颗粒中。结构活性研究表明，芳香环上的3′-或4′- oh基团增强了抑制效能，而这些位置上的Me或OMe基团则降低了抑制效能。在芳香环的4′位置上卤素取代导致抑制能力逐渐增加，与卤素的电子给体能力平行。NH(2)上的取代基和烷基链3位上的取代基降低了抑制效能。对含有酪胺和神经毒素1-甲基-4-苯基吡啶的APP衍生物的结构-活性比较分析表明，侧链的柔韧性和NH(2)基团的相对取向可能是底物通过bVMAT有效运输的关键。这些抑制剂的bVMAT亲和力与DA和其他药理活性胺的相似，表明它们适用于单胺转运体的结构-活性和机制研究，也可用于模拟安非他明相关衍生物的作用机制。
A series of 3-amino-2-phenylpropene (APP) derivatives have been synthesized and characterized as novel competitive inhibitors, with K(i) values in the microM range, for the bovine chromaffin granule membrane monoamine transporter(s) (bVMAT). Although, these inhibitors are structurally similar to the bVMAT substrate tyramine, none of them were measurably transported into the granule. Structure-activity studies have revealed that, while the 3'- or 4'-OH groups on the aromatic ring enhance the inhibition potency, Me or OMe groups in these positions reduce the inhibition potency. Halogen substitution on the 4'-position of the aromatic ring causes gradual increase of the inhibition potency parallel to the electron donor ability of the halogen. Substituents on the NH(2) as well as on the 3-position of the alkyl chain reduce the inhibition potency. Comparative structure-activity analyses of APP derivatives with tyramine and the neurotoxin 1-methyl-4-phenylpyridinium suggest that the flexibility of the side chain and the relative orientation of the NH(2) group may be critical for the efficient transport of the substrate through the bVMAT. Comparable bVMAT affinities of these inhibitors to that of DA and other pharmacologically active amines suggest that they are suitable for the structure-activity and mechanistic studies of monoamine transporters and may also be useful in modeling the mechanism of action of amphetamine-related derivatives.