Format

Send to

Choose Destination
Trends Pharmacol Sci. 2018 Jun;39(6):560-572. doi: 10.1016/j.tips.2018.03.004. Epub 2018 Apr 5.

Peripheral Serotonin Synthesis as a New Drug Target.

Author information

1
Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10, 13125 Berlin-Buch, Germany; University of Lübeck, Institute for Biology, Ratzeburger Allee 160, 23562 Lübeck, Germany.
2
Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10, 13125 Berlin-Buch, Germany; University of Lübeck, Institute for Biology, Ratzeburger Allee 160, 23562 Lübeck, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany; Charité University Medicine, Charitéplatz 1, 10117 Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany. Electronic address: mbader@mdc-berlin.de.

Abstract

The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood-brain barrier to specifically block peripheral 5-HT synthesis. They showed therapeutic efficacy in several rodent disease models, and telotristat ethyl is the first TPH inhibitor to be approved for the treatment of carcinoid syndrome. We review this development and discuss further therapeutic options for these compounds.

KEYWORDS:

carcinoid syndrome; serotonin; small-molecule inhibitor; telotristat ethyl; tryptophan hydroxylase

PMID:
29628275
DOI:
10.1016/j.tips.2018.03.004
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center