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

• 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 Compound1(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 of1showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of1, 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Keyword

aromatic amino acid hydroxylases

differential scanning fluorimetry

enzyme inhibitors

kinetics

TPH1

TPH2

tryptophan

Publication and Content Type

ref (subject category)

art (subject category)