In the present study a series of tetrahydroisoquinoline derivatives were synthesized and evaluated for their activity towards three ABC transporters, P-gp, MRP1 and BCRP. The compounds proved to be selective against P-gp. One of them, 8b, displayed activity in the nanomolar range (EC₅₀ = 94 nM). Thus, compound 8b was tested for its ability to restore the cytotoxic activity of a well-known anti-cancer agent and P-gp substrate, doxorubicin, as first proof of concept. Moreover, compound 8b was also tested in an in vitro model of competent gastro-intestinal (GI) barrier (Caco-2 cells) for its ability to inhibit P-gp, present on luminal side, and increase the apical-to-basolateral transport of several structurally uncorrelated drugs, belonging to different therapeutic areas but actively excreted by P-gp. Notably the transport of the drugs across the GI barrier was increased by a concentration of 8b devoid of toxicity and of perturbing effects on barrier function. An in vitro simulated digestion process was set up: interestingly the effect 8b on the transport of digoxin was preserved also after the simulated digestion process. This result may suggest 8b as a safe and effective P-gp modulator that can increase the bioavailability of a wide-spectrum of drugs administered per os, improving their transport across the GI barrier.

在本研究中，合成了一系列四氢异喹啉衍生物，并评估了它们对三种ABC转运蛋白P-gp，MRP1和BCRP的活性。该化合物被证明对P-gp具有选择性。其中之一8b表现出纳摩尔范围内的活性（EC ₅₀ = 94 nM）。因此，测试化合物8b恢复众所周知的抗癌剂和P-gp底物阿霉素的细胞毒性活性的能力，这是概念的第一个证明。此外，化合物8b在感受态胃肠道（GI）屏障（Caco-2细胞）的体外模型中也测试了其抑制P-gp的能力，该能力存在于腔侧，并增加了几种结构不相关的顶突向基底外侧的转运药物，属于不同的治疗领域，但被P-gp主动排泄。值得注意的是，通过8b的浓度增加了药物通过GI屏障的转运，该浓度没有毒性，也没有对屏障功能的干扰作用。建立了体外模拟消化过程：有趣的是，在模拟消化过程之后也保留了8b对地高辛运输的影响。该结果可能表明8b作为一种安全和有效的P-gp的调制器，可以增加的施用的药物广谱的生物利用度口服，穿过GI屏障改进其输送。