Incorporation of a Biguanide Scaffold Enhances Drug Uptake by Organic Cation Transporters 1 and 2.
Incorporation of a Biguanide Scaffold Enhances Drug Uptake by Organic Cation Transporters 1 and 2.
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DOI：
10.1021/acs.molpharmaceut.7b00285
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发表时间：
2017-08-07
影响因子：
4.9
通讯作者：
Shu Y
中科院分区：
文献类型：
--
作者：
Obianom ON;Coutinho AL;Yang W;Yang H;Xue F;Shu Y
膜转运蛋白在许多内源性和外源性化合物的转运中起着重要作用。对转运体底物要求的了解使得进一步开发利用它们来确保组织渗透的药物成为可能。在这项研究中，我们证明了双胍功能的包含可以增强有机阳离子转运体1和2 （OCT1和OCT2）的摄取。我们合成了18对结构多样的化合物，每对化合物由一个母氨基化合物和它的双胍类似物组成；然后评估它们在过表达人OCT1或OCT2的HEK293细胞中的细胞摄取。我们的研究结果表明，双胍的加入显著改善了OCT1-和OCT2-介导的大多数化合物的转运。双胍类化合物还抑制了两种转运体1-甲基-4-苯基吡啶（MPP+）和二甲双胍的原型底物的摄取。我们发现分子量、分子体积、Log D （pH 7.4）和可达表面积是OCT2底物的重要决定因素，但这些参数都不是OCT1的重要因素。更重要的是，在两种细胞系中，MPP+摄取的抑制与二甲双胍摄取的抑制呈线性相关。综上所述，我们得出结论，在OCT1和OCT2的非底物中包含双胍支架增加了它们成为这些转运体的底物和抑制剂的倾向。
Membrane transporters play a significant role in the transport of many endogenous and exogenous compounds. The knowledge of transporter substrate requirements has allowed further development of drugs that utilize them to ensure tissue permeation. In this study, we demonstrate that inclusion of a biguanide functionality can potentiate uptake by the organic cation transporters 1 and 2 (OCT1 and OCT2). We synthesized 18 pairs of structurally diverse compounds, each pair consisting of a parent amino compound and its biguanide analog; and then assessed their cellular uptake in HEK293 cells overexpressing human OCT1 or OCT2. Our results show that addition of the biguanide significantly improved OCT1- and OCT2- mediated transport for the majority of compounds. The biguanides also inhibited the uptake of prototypical substrates of both transporters, 1-methyl-4-phenylpyridinium (MPP+) and metformin. We found that molecular weight, molecular volume, Log D (pH 7.4), and accessible surface area were important determinants of OCT2 substrates, but none of these parameters was a significant factor for OCT1. More so, the inhibition of MPP+ uptake correlated linearly with that of metformin uptake for the tested biguanides in both cell lines. Taken together, we conclude that the inclusion of the biguanide scaffold in nonsubstrates of OCT1 and OCT2 increase their propensity to become substrates and inhibitors for these transporters.
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影响因子：
2.6
作者：
Gong L;Goswami S;Giacomini KM;Altman RB;Klein TE
通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
2013-01-01
影响因子：
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作者：
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通讯作者：
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影响因子：
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