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Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis.

Authors
  • Betari, Nibal1
  • Sahlholm, Kristoffer2
  • Ishizuka, Yuta1
  • Teigen, Knut1
  • Haavik, Jan1, 3
  • 1 Department of Biomedicine, University of Bergen, Jonas Lies vei 91, Postboks 7804, 5020 Bergen, Norway. , (Norway)
  • 2 Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, Johan Bures väg 12, 901 87 Umeå, Sweden. , (Sweden)
  • 3 Division of Psychiatry, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway. , (Norway)
Type
Published Article
Journal
Future Medicinal Chemistry
Publisher
"Future Science, LTD"
Publication Date
Aug 01, 2020
Volume
12
Issue
16
Pages
1461–1474
Identifiers
DOI: 10.4155/fmc-2020-0127
PMID: 32752885
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound 1 (2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure-activity relationships studies revealed several analogs of 1 showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.

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