Peripheral Serotonin Synthesis as a New Drug Target

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. 5-HT is synthesized by two tryptophan hydroxylases, TPH1 in ECs of the gut and TPH2 in hindbrain raphe nuclei. EC-derived 5-HT is transported by circulating platelets and released upon their activation. Moreover, there is local TPH1 and 5-HT synthesis in lung, pancreatic β cells, and adipocytes, as well as local TPH2-mediated 5-HT synthesis in enteric neurons. TPH1-derived 5-HT causes the gastrointestinal symptoms associated with carcinoid tumors (carcinoid syndrome) and is thought to be involved in several other disorders such as pulmonary hypertension, inflammatory and fibrotic diseases, thrombosis, and obesity. Its effects on osteoporosis are controversial. Inhibition of peripheral 5-HT synthesis is a novel therapeutic strategy for these diseases. TPH2-mediated 5-HT synthesis in the brain should be spared because its inhibition would cause adverse effects such as depression. Telotristat ethyl is the first TPH inhibitor with FDA approval for the treatment of carcinoid syndrome. This and other compounds of this novel drug class need to prove their efficacy for the treatment of other diseases in future preclinical and clinical studies. The clinical use of telotristat ethyl and other non-selective TPH inhibitors will clarify whether their exclusion from the brain is sufficient to avoid adverse central nervous system effects, or if it will be necessary to develop novel compounds which do not inhibit TPH2. The first such TPH1-selective compounds were recently discovered, but their allosteric mechanisms of action and efficacy remain to be further validated.