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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract

Qingyun Liu, Qi Yang, Weimei Sun, Pete Vogel, William Heydorn, Xiang-Qing Yu, Zhixiang Hu, Wangsheng Yu, Brandie Jonas, Randy Pineda, Valerie Calderon-Gay, Michael Germann, Emily O'Neill, Robert Brommage, Emily Cullinan, Ken Platt, Alan Wilson, Dave Powell, Arthur Sands, Brian Zambrowicz and Zhi-cai Shi
Journal of Pharmacology and Experimental Therapeutics April 2008, 325 (1) 47-55; DOI: https://doi.org/10.1124/jpet.107.132670
Qingyun Liu
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Qi Yang
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Weimei Sun
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Pete Vogel
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William Heydorn
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Xiang-Qing Yu
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Zhixiang Hu
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Wangsheng Yu
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Brandie Jonas
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Randy Pineda
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Valerie Calderon-Gay
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Michael Germann
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Emily O'Neill
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Robert Brommage
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Emily Cullinan
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Ken Platt
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Alan Wilson
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Dave Powell
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Arthur Sands
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Brian Zambrowicz
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Zhi-cai Shi
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Abstract

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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.132670.

  • ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); TPH, tryptophan hydroxylase; EC, enterochromaffin; GI, gastrointestinal; CNS, central nervous system; pCPA, para-chlorophenylalanine; KOS, knockout shuttle; 5-HIAA, 5-hydroxyindole acetic acid; PBS, phosphate-buffered saline; ANOVA, analysis of variance; 5-HT3, 5-hydroxytryptamine receptor 3; LP-533401, (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; LP-615819, (2S)-ethyl 2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; FIAU, 1-2′-deoxy-2′-fluoro-β-d-arabinofuranosyl-5-iodouracil.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received October 8, 2007.
    • Accepted January 9, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract

Qingyun Liu, Qi Yang, Weimei Sun, Pete Vogel, William Heydorn, Xiang-Qing Yu, Zhixiang Hu, Wangsheng Yu, Brandie Jonas, Randy Pineda, Valerie Calderon-Gay, Michael Germann, Emily O'Neill, Robert Brommage, Emily Cullinan, Ken Platt, Alan Wilson, Dave Powell, Arthur Sands, Brian Zambrowicz and Zhi-cai Shi
Journal of Pharmacology and Experimental Therapeutics April 1, 2008, 325 (1) 47-55; DOI: https://doi.org/10.1124/jpet.107.132670

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract

Qingyun Liu, Qi Yang, Weimei Sun, Pete Vogel, William Heydorn, Xiang-Qing Yu, Zhixiang Hu, Wangsheng Yu, Brandie Jonas, Randy Pineda, Valerie Calderon-Gay, Michael Germann, Emily O'Neill, Robert Brommage, Emily Cullinan, Ken Platt, Alan Wilson, Dave Powell, Arthur Sands, Brian Zambrowicz and Zhi-cai Shi
Journal of Pharmacology and Experimental Therapeutics April 1, 2008, 325 (1) 47-55; DOI: https://doi.org/10.1124/jpet.107.132670
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