Sökning: onr:"swepub:oai:DiVA.org:umu-174624" >
Discovery and biolo...
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- aromatic amino acid hydroxylases
- differential scanning fluorimetry
- enzyme inhibitors
- kinetics
- TPH1
- TPH2
- tryptophan
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas