Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an City, Shaanxi Province, China.
College of Basic Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Xianyang City, Shaanxi Province, China.
Chem Biol Drug Des. 2018 Jan;91(1):202-212. doi: 10.1111/cbdd.13071. Epub 2017 Aug 17.
Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract. Two distinct tryptophan hydroxylases (TPH), TPH1 and TPH2, are the rate-limiting enzymes in the 5-HT biosynthesis process. TPH1 expression is mainly limited in the enterochromaffin cells and distributed in peripheries such as the skin and gut, while TPH2 is the predominant isoform in the CNS. In this study, mol002291 was screened as a drug-like compound from the TCM database for the inhibitor of TPH. After the enzymological analysis of mol002291, the analgesic effect of mol002291 was also further investigated in a PI-IBS visceral hyperalgesia rat model. Results from kinetic analysis showed that mol002291 specifically inhibited the TPH1 but did not act on TPH2, and the inhibitory action displayed characteristics of competitive inhibition. In addition, the results from abdominal withdrawal reflex (AWR) tests and electromyography (EMG) recordings showed that mol002291 significantly (p < .05) alleviated the visceral hyperalgesia. This result is entirely consistent with the fact that mol002291 significantly decreased the 5-HT content. These data demonstrated that mol002291 can attenuate visceral hyperalgesia mediated via reducing colonic 5-HT content. More important is that mol002291 could be developed as a novel prodrug and offer therapeutic avenues for the diseases where there is dysregulation of peripheral serotonergic pathways.
5-羟色胺（5-HT）是胃肠道中重要的神经递质和旁分泌信号分子。两种不同的色氨酸羟化酶（TPH），TPH1 和 TPH2，是 5-HT 生物合成过程中的限速酶。TPH1 表达主要局限于肠嗜铬细胞，分布于皮肤和肠道等外周组织，而 TPH2 是中枢神经系统中的主要同工酶。在这项研究中，从中药数据库中筛选出 mol002291 作为 TPH 的抑制剂。在对 mol002291 进行酶学分析后，还进一步在 PI-IBS 内脏痛觉过敏大鼠模型中研究了 mol002291 的镇痛作用。动力学分析结果表明，mol002291 特异性抑制 TPH1 但不作用于 TPH2，抑制作用表现出竞争性抑制的特征。此外，腹壁退缩反射（AWR）试验和肌电图（EMG）记录结果表明，mol002291 显著（p<.05）减轻了内脏痛觉过敏。这一结果与 mol002291 显著降低 5-HT 含量的事实完全一致。这些数据表明，mol002291 可以通过减少结肠 5-HT 含量来减轻内脏痛觉过敏。更重要的是，mol002291 可以开发为一种新型前药，为外周 5-羟色胺能途径失调的疾病提供治疗途径。
