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

@article{Liu2008DiscoveryAC,
  title={Discovery and Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis in the Gastrointestinal Tract},
  author={Qingyun Liu and Qi Melissa Yang and Weimei Sun and P. Vogel and William E. Heydorn and Xiang-Qing Yu and Zhixiang Hu and Wangsheng Yu and Brandie M. Jonas and R Pineda and Valerie Calderon-Gay and Micha Germann and Emily O'Neill and Robert Brommage and Emily B. Cullinan and Ken Platt and Alan G. E. Wilson and David R. Powell and Arthur T. Sands and Brian Zambrowicz and Zhi-cai Shi},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2008},
  volume={325},
  pages={47 - 55}
}
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… 
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Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis.

This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin and noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin.

Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis

Analysis of the structural data showed that each of the three inhibitors fills the tryptophan binding pocket of TPH1 without reaching into the binding site of the cofactor pterin, and induces major conformational changes of the enzyme.

Effect of the Tryptophan Hydroxylase Inhibitor Telotristat on Growth and Serotonin Secretion in 2D and 3D Cultured Pancreatic Neuroendocrine Tumor Cells

The results suggest that telotristat is an effective drug for serotonin inhibition, but the effectiveness of its combination with SST2 (somatostatin receptor subtype 2)-preferring SSA should be evaluated in more detail.
...

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