MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, PR China; Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Zhanjiang, 524000, PR China.
MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, PR China.
J Pharm Sci. 2021 Aug;110(8):3011-3019. doi: 10.1016/j.xphs.2021.04.011. Epub 2021 Apr 21.
Vortioxetine (Vot) is an effective antidepressant with unique mechanisms exerting multi-target effects. However, severe side-effects such as nausea and vomiting are commonly experienced under conditions of long-term administration. Eight amino acid modified Vot derivatives were designed and prepared in this study. Similar or lower binding affinities of the modified compounds to the serotonin transporter (SERT) than Vot was observed in the 4-(4-(dimethylamino)-styrl)-N-methylpyridinium (ASP) uptake assay on RBL-2H3 cells. Additionally, the majority of derivatives remained sufficiently stable in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), indicating achievement of intestinal absorption in the modified form. Afterwards, all derived compounds exhibited slower hepatic clearance and a longer half-life, compared to the parent drug Vot. Notably, threonine-modified 3f exhibited significantly lower activity to SERT, serine-modified 3e showed the fastest degradation rate in rat plasma, with hydrolysis to an extent of 50% in 10 min, and better pharmacokinetic properties in rat, including C, t, and especially AUC, which was ~3-fold higher relative to the parent compound. Although, no clear understanding of SARs has been obtained, modification of Vot with amino acids containing hydroxyl groups may be beneficial to reduce the gastrointestinal side effect of Vot or obtain better pharmacokinetic properties, providing some ideas for the further study in the future.
文拉法辛（Vot）是一种有效的抗抑郁药，具有独特的多靶点作用机制。然而，长期给药时，常出现严重的副作用，如恶心和呕吐。本研究设计并制备了 8 种氨基酸修饰的文拉法辛衍生物。在 RBL-2H3 细胞上的 4-（4-（二甲基氨基）-苯乙烯基）-N-甲基吡啶鎓（ASP）摄取测定中，与文拉法辛相比，修饰化合物对 5-羟色胺转运体（SERT）的结合亲和力相似或降低。此外，大多数衍生物在模拟胃液（SGF）和模拟肠液（SIF）中保持足够的稳定性，表明在修饰形式下实现了肠吸收。之后，与母体药物文拉法辛相比，所有衍生化合物均表现出较慢的肝清除率和较长的半衰期。值得注意的是，苏氨酸修饰的 3f 对 SERT 的活性显著降低，丝氨酸修饰的 3e 在大鼠血浆中的降解速度最快，在 10 分钟内水解至 50%，在大鼠中的药代动力学特性更好，包括 C、t，特别是 AUC，与母体化合物相比约高 3 倍。尽管尚未清楚了解 SAR，但用含有羟基的氨基酸修饰文拉法辛可能有助于降低文拉法辛的胃肠道副作用或获得更好的药代动力学特性，为今后的进一步研究提供了一些思路。
