Open AccessDiscovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis
Author(s) -
Nibal Betari,
Kristoffer Sahlholm,
Yuta Ishizuka,
Knut Teigen,
Jan Haavik
Publication year - 2020
Publication title -
future medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.708
H-Index - 69
eISSN - 1756-8927
pISSN - 1756-8919
DOI - 10.4155/fmc-2020-0127
Subject(s) - serotonin , tryptophan , potency , chemistry , mode of action , docking (animal) , pharmacology , tryptophan hydroxylase , tetrahydrobiopterin , enzyme , biochemistry , in vitro , amino acid , stereochemistry , biology , cofactor , medicine , receptor , nursing , serotonergic
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(2 H)-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.