立体选择性是众所周知的,并且在药物代谢和受体结合中非常显著。然而,对药物膜运输中的立体选择性知之甚少。这里,我们表征了人单胺转运蛋白对手性苯乙胺衍生物的立体选择性细胞摄取(NET,DAT,和SERT)和有机阳离子转运蛋白(OCT1、OCT2和OCT3)。密切相关的转运蛋白之间的立体选择性差异很大。高亲和力单胺转运蛋白(MAT)显示出高达2.4倍的去甲肾上腺素和肾上腺素以及许多类似物的立体选择性摄取。NET和DAT优先转运(S)-去甲肾上腺素,SERT优选(R)-对映体。相比之下,NET和DAT对(R)-肾上腺素的转运较高,对(S)-肾上腺素的转运较高。一般来说,MAT的立体选择性低于预期,原因是它们对几种儿茶酚胺的高亲和力以及某些用作抗抑郁药的抑制剂的高立体选择性。此外,OCTs的立体选择性差异很大。虽然OCT1显示几乎没有立体选择性摄取,OCT2的特征在于对苯乙胺的大多数(R)-对映体的大约2倍的偏好。相比之下,OCT3转运去甲肾上腺素和去氧肾上腺素,其(R)对映体的偏好为3.9倍和3.3倍,分别,而对羟基化的章鱼胺和辛弗林没有显示出立体选择性的OCT3转运。总之,我们的数据表明,立体选择性是高度转运蛋白-底物特异性的,甚至在同源转运蛋白之间也是高度多样化的。
Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters.