PT  - JOURNAL ARTICLE
AU  - Qingyun Liu
AU  - Qi Yang
AU  - Weimei Sun
AU  - Pete Vogel
AU  - William Heydorn
AU  - Xiang-Qing Yu
AU  - Zhixiang Hu
AU  - Wangsheng Yu
AU  - Brandie Jonas
AU  - Randy Pineda
AU  - Valerie Calderon-Gay
AU  - Michael Germann
AU  - Emily O'Neill
AU  - Robert Brommage
AU  - Emily Cullinan
AU  - Ken Platt
AU  - Alan Wilson
AU  - Dave Powell
AU  - Arthur Sands
AU  - Brian Zambrowicz
AU  - Zhi-cai Shi
TI  - Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract
AID  - 10.1124/jpet.107.132670
DP  - 2008 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 47--55
VI  - 325
IP  - 1
4099  - http://jpet.aspetjournals.org/content/325/1/47.short
4100  - http://jpet.aspetjournals.org/content/325/1/47.full
SO  - J Pharmacol Exp Ther2008 Apr 01; 325
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics