Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract
Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract
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DOI：
10.1124/jpet.107.132670
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Shi, Zhi-Cai
中科院分区：
文献类型：
--
作者：
Liu, Qingyun;Yang, Qi;Shi, Zhi-Cai
5-羟色胺（血清素）(5-HT) 是一种具有中枢和外周功能的神经递质，包括调节情绪、食欲、血流动力学、胃肠 (GI) 感觉、分泌和运动。它的合成是由色氨酸羟化酶（TPH）引发的。已发现 TPH 的两种亚型：TPH1 主要在胃肠道的肠嗜铬细胞中表达，TPH2 仅在神经元细胞中表达。缺乏 Tph1 的小鼠血液和胃肠道中几乎不含 5-HT，而大脑中的 5-HT 含量保持正常。由于已知 GI 5-HT 在正常和病理生理学中发挥重要作用，因此我们着手发现并表征选择性抑制 GI 5-HT 生物合成的新型化合物。在这里，我们描述了一系列抑制剂中的两种，它们在生化和基于细胞的测定中均对 TPH 活性有效。此类化合物在对胃肠道血清素产生的药代动力学和药效学影响方面具有独特的性质。与 Tph1 敲除结果类似，这些 TPH 抑制剂能够选择性降低小鼠胃肠道中的 5-HT 水平，而不影响大脑中的 5-HT 水平。此外，在化疗引起的呕吐的雪貂模型中施用这些化合物会导致肠道血清素水平适度降低并减少呕吐反应。这些发现表明，胃肠道特异性 TPH 抑制剂可能为与胃肠道血清素能系统失调相关的各种胃肠道疾病（例如化疗引起的呕吐和肠易激综合征）提供新的治疗方法。
5-Hydroxytryptamine (serotonin) (5-HT) is a neurotransmitter with both central and peripheral functions, including the modulation of mood, appetite, hemodynamics, gastrointestinal (GI) sensation, secretion, and motility. Its synthesis is initiated by the enzyme tryptophan hydroxylase (TPH). Two isoforms of TPH have been discovered: TPH1, primarily expressed in the enterochromaffin cells of the gastrointestinal tract, and TPH2, expressed exclusively in neuronal cells. Mice lacking Tph1 contain little to no 5-HT in the blood and GI tract while maintaining normal levels in the brain. Because GI 5-HT is known to play important roles in normal and pathophysiology, we set out to discover and characterize novel compounds that selectively inhibit biosynthesis of GI 5-HT. Here, we describe two of a series of these inhibitors that are potent for TPH activity both in biochemical and cell-based assays. This class of compounds has unique properties with respect to pharmacokinetic and pharmacodynamic effects on GI serotonin production. Similar to the Tph1 knockout results, these TPH inhibitors have the ability to selectively reduce 5-HT levels in the murine GI tract without affecting brain 5-HT levels. In addition, administration of these compounds in a ferret model of chemotherapy-induced emesis caused modest reductions of intestinal serotonin levels and a decreased emetic response. These findings suggest that GI-specific TPH inhibitors may provide novel treatments for various gastrointestinal disorders associated with dysregulation of the GI serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.