Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract

The Journal of Pharmacology and Experimental Therapeutics
Qingyun LiuZhi-Cai Shi

Abstract

5-Hydroxytryptamine (serotonin) (5-HT) is a neurotransmitter with both central and peripheral functions, including the modulation of mood, appetite, hemodynamics, gastrointestinal (GI) sensation, secretion, and motility. Its synthesis is initiated by the enzyme tryptophan hydroxylase (TPH). Two isoforms of TPH have been discovered: TPH1, primarily expressed in the enterochromaffin cells of the gastrointestinal tract, and TPH2, expressed exclusively in neuronal cells. Mice lacking Tph1 contain little to no 5-HT in the blood and GI tract while maintaining normal levels in the brain. Because GI 5-HT is known to play important roles in normal and pathophysiology, we set out to discover and characterize novel compounds that selectively inhibit biosynthesis of GI 5-HT. Here, we describe two of a series of these inhibitors that are potent for TPH activity both in biochemical and cell-based assays. This class of compounds has unique properties with respect to pharmacokinetic and pharmacodynamic effects on GI serotonin production. Similar to the Tph1 knockout results, these TPH inhibitors have the ability to selectively reduce 5-HT levels in the murine GI tract without affecting brain 5-HT levels. In addition, administration of these co...Continue Reading

References

Feb 1, 1990·Canadian Journal of Physiology and Pharmacology·P L AndrewsL Maskell
Jun 1, 1970·Biochemical Pharmacology·L J Weber
Nov 23, 1967·The New England Journal of Medicine·K EngelmanA Sjoerdsma
Dec 30, 1998·Japanese Journal of Pharmacology·J A RuddR J Naylor
Jan 15, 1999·Analytical Biochemistry·G R Moran, P F Fitzpatrick
Mar 18, 1999·The New England Journal of Medicine·M H Kulke, R J Mayer
Aug 4, 1999·Nature Genetics·B ZhengA Bradley
Sep 28, 2000·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·C Lindley, P Blower
Jan 4, 2003·Science·Diego J WaltherMichael Bader
Nov 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Francine CôtéGuilan Vodjdani
Feb 13, 2004·Biological Psychiatry·Paresh D PatelSharon Burke
Mar 31, 2005·Journal of Clinical Gastroenterology·Michael D Gershon
Jan 21, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Konstantin V SalojinTamas Oravecz

❮ Previous
Next ❯

Citations

Jul 17, 2008·Current Gastroenterology Reports·Brian Garvin, John W Wiley
May 24, 2011·Nature Medicine·Yajun CuiAlexander G Robling
Jun 9, 2010·Nature Reviews. Drug Discovery·Sarah Crunkhorn
Jun 26, 2013·Nature Reviews. Gastroenterology & Hepatology·Gary M Mawe, Jill M Hoffman
Jan 1, 2009·Current Opinion in Endocrinology, Diabetes, and Obesity·Michael Camilleri
Mar 11, 2010·Physiological Genomics·Rachael S HagemanGudrun A Brockmann
Sep 9, 2010·The Journal of Clinical Endocrinology and Metabolism·Michael Bliziotes
Jul 4, 2012·International Journal of Molecular Sciences·Liang OuyangMingli Xiang
Jul 23, 2013·Gut·Alon D Levin, Gijs R van den Brink
Nov 16, 2010·Annual Review of Medicine·Gerard Karsenty, Vijay K Yadav
Jun 14, 2015·FEBS Letters·Rabih El-MerahbiGrzegorz Sumara
Mar 27, 2012·Nuclear Medicine and Biology·Csaba JuhászOtto Muzik
Jun 28, 2011·Gastroenterology·Jan TackGuy Boeckxstaens
Feb 22, 2011·Gastroenterology Clinics of North America·Monthira ManeerattanapornWilliam D Chey
Aug 9, 2008·Neuropharmacology·Robin Spiller
Oct 23, 2012·Cell Metabolism·Grzegorz SumaraGerard Karsenty
May 25, 2011·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Hiroyuki InosePatricia Ducy
Apr 14, 2015·Nature Communications·Chang-Myung OhHail Kim
Feb 26, 2013·Biochemical Pharmacology·Guo-Lin Chen, Gregory M Miller
Oct 21, 2016·FEBS Open Bio·Kasper D TidemandGünther H Peters
Sep 3, 2016·Journal of Medicinal Chemistry·Mark A T Blaskovich
Nov 9, 2016·Scandinavian Journal of Clinical and Laboratory Investigation·Qiu-Shi WeiWei-Min Deng
Nov 8, 2016·Expert Opinion on Pharmacotherapy·Angela LamarcaJuan W Valle
Dec 16, 2016·Expert Opinion on Therapeutic Targets·Kai WaløenJan Haavik
Mar 2, 2016·Veterinary Pathology·P VogelR Brommage
Mar 7, 2017·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·J A UrangaR Abalo
Jan 4, 2017·Bioorganic & Medicinal Chemistry Letters·Daniel R GoldbergWilliam Zavadoski
Apr 28, 2018·Nature Reviews. Drug Discovery·Jarkko RautioMichael J Hageman
Jan 20, 2018·Future Oncology·Joseph S Dillon, Chandrikha Chandrasekharan
Sep 26, 2013·The American Journal of Gastroenterology·Helmut GrasbergerJuanita L Merchant
Jan 20, 2012·Nature·Gérard Karsenty, Mathieu Ferron
Jan 14, 2018·Endocrine-related Cancer·Marianne PavelRocio Garcia-Carbonero
Oct 24, 2018·American Journal of Physiology. Endocrinology and Metabolism·Samantha R WeaverLaura L Hernandez
Oct 5, 2010·American Journal of Physiology. Gastrointestinal and Liver Physiology·Brecht GeeraertsJan Tack

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.