Shinozaki Yusuke, Tega Yuma, Akanuma Shin-Ichi, Hosoya Ken-Ichi
Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Pharmaceuticals (Basel). 2023 Mar 13;16(3):435. doi: 10.3390/ph16030435.
Blood-to-retina transport across the inner blood-retinal barrier (BRB) is a key determinant of retinal drug concentration and pharmacological effect. Recently, we reported on the amantadine-sensitive drug transport system, which is different from well-characterized transporters, at the inner BRB. Since amantadine and its derivatives exhibit neuroprotective effects, it is expected that a detailed understanding of this transport system would lead to the efficient retinal delivery of these potential neuroprotective agents for the treatment of retinal diseases. The objective of this study was to characterize the structural features of compounds for the amantadine-sensitive transport system. Inhibition analysis conducted on a rat inner BRB model cell line indicated that the transport system strongly interacts with lipophilic amines, especially primary amines. In addition, lipophilic primary amines that have polar groups, such as hydroxy and carboxy groups, did not inhibit the amantadine transport system. Furthermore, certain types of primary amines with an adamantane skeleton or linear alkyl chain exhibited a competitive inhibition of amantadine uptake, suggesting that these compounds are potential substrates for the amantadine-sensitive drug transport system at the inner BRB. These results are helpful for producing the appropriate drug design to improve the blood-to-retina delivery of neuroprotective drugs.
血液通过视网膜内血视网膜屏障（BRB）向视网膜的转运是决定视网膜药物浓度和药理作用的关键因素。最近，我们报道了在内侧BRB处存在一种对金刚烷胺敏感的药物转运系统，该系统不同于已被充分表征的转运体。由于金刚烷胺及其衍生物具有神经保护作用，因此预计详细了解该转运系统将有助于这些潜在神经保护剂有效递送至视网膜，用于治疗视网膜疾病。本研究的目的是表征对金刚烷胺敏感的转运系统的化合物结构特征。在大鼠内侧BRB模型细胞系上进行的抑制分析表明，该转运系统与亲脂性胺类，尤其是伯胺类，有强烈相互作用。此外，带有羟基和羧基等极性基团的亲脂性伯胺并不抑制金刚烷胺转运系统。此外，某些具有金刚烷骨架或直链烷基链的伯胺类对金刚烷胺摄取表现出竞争性抑制，这表明这些化合物可能是内侧BRB处对金刚烷胺敏感的药物转运系统的潜在底物。这些结果有助于进行适当的药物设计，以改善神经保护药物的血视网膜递送。
