Author: Winkler, Lars ; Bader, Michael ; Wasinska-Kalwa, Malgorzata ; Nazaré, Marc ; Schütz, Anja ; Specker, Edgar ; Oder, Andreas ; von Kries, Jens Peter ; Pleimes, Dirk ; Wesolowski, Radoslaw ; Alenina, Natalia ; Heinemann, Udo ; Mallow, Keven ; Matthes, Susann

Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound 32 (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.

01 Feb 2023·Psychopharmacology

Involvement of the serotonergic system in the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine in mice

Article

Author: Lenardão, Eder João ; Penteado, Filipe ; Brüning, César Augusto ; Besckow, Evelyn Mianes ; Gomes, Caroline Signorini ; Bortolatto, Cristiani Folharini ; Pires, Camila Simões ; Nunes, Gustavo D'Avila ; Presa, Marcelo Heinemann ; da Rocha, Marcia Juciele

RATIONALEDepression is a mental disorder that affects approximately 280 million people worldwide. In the search for new treatments for mood disorders, compounds containing selenium and indolizine derivatives show promising results.OBJECTIVES AND METHODSTo evaluate the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) (0.5-50 mg/kg, intragastric-i.g.) on the tail suspension test (TST) and the forced swim test (FST) in adult male Swiss mice and to elucidate the role of the serotonergic system in this effect through pharmacological and in silico approaches, as well to evaluate acute oral toxicity at a high dose (300 mg/kg).RESULTSMeSeI administered 30 min before the FST and the TST reduced immobility time at doses from 1 mg/kg and at 50 mg/kg and increased the latency time for the first episode of immobility, demonstrating an antidepressant-like effect. In the open field test (OFT), MeSeI did not change the locomotor activity. The antidepressant-like effect of MeSeI (50 mg/kg, i.g.) was prevented by the pre-treatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100 mg/kg, intraperitoneally-i.p. for 4 days), with ketanserin, a 5-HT_2A/2C receptor antagonist (1 mg/kg, i.p.), and with GR113808, a 5-HT₄ receptor antagonist (0.1 mg/kg, i.p.), but not with WAY100635, a selective 5-HT_1A receptor antagonist (0.1 mg/kg, subcutaneous-s.c.) and ondansetron, a 5-HT₃ receptor antagonist (1 mg/kg, i.p.). MeSeI showed a binding affinity with 5-HT_2A, 5 -HT_2C, and 5-HT₄ receptors by molecular docking. MeSeI (300 mg/kg, i.g.) demonstrated low potential to cause acute toxicity in adult female Swiss mice.CONCLUSIONIn summary, MeSeI exhibits an antidepressant-like effect mediated by the serotonergic system and could be considered for the development of new treatment strategies for depression.

01 Jan 2006·Headache: The Journal of Head and Face PainQ2 · MEDICINE

Serotonin Depletion, Cortical Spreading Depression, and Trigeminal Nociception

Q2 · MEDICINE

Article

Author: Supornsilpchai, Weera ; Sanguanrangsirikul, Sompol ; Srikiatkhachorn, Anan ; Maneesri, Supang

Background.—The attack of migraine has been observed to be associated with low level of serotonin (5‐HT). Although the mechanism underlying this relationship is still unclear, change in cortical excitability or susceptibility of trigeminal system is a possible explanation.Objectives.—The aim was to study the effect of 5‐HT depletion on the development of cortical spreading depression (CSD) and CSD‐evoked trigeminal nociception.Methods.—Wistar rats were separated into low 5‐HT and control groups (eight rats each). 5‐HT was depleted by administration of para‐chlorophenylalanine, a tryptophan hydroxylase inhibitor. CSD was induced by applying 3 mg of potassium chloride on parietal cortex. Cortical activity was monitored for 1 hour. Trigeminal nociception was determined using number of Fos‐immunoreactive (Fos‐IR) neurons in trigeminal nucleus caudalis as the indicator.Results.—Application of KCl led to the development of series of depolarization shift characteristics for CSD. The development of these CSD waves was enhanced in low 5‐HT state. The area under curve of each CSD wave and the number of CSD waves occurring within 1 hour were greater in low 5‐HT group. No significant change in peak amplitude and duration of CSD wave was observed. The numbers of Fos‐IR cells on ipsilateral and contralateral trigeminal nucleus caudalis were significantly greater in the low 5‐HT group than those of the controls.Conclusion.—Our findings indicate that 5‐HT depletion enhances CSD‐induced trigeminal nociception by increasing the cortical excitability and sensitivity of trigeminal nociceptive system. These findings may provide a better understanding regarding the relationship between low 5‐HT and clinical headaches.

100 Deals associated with Tuberculosis tryptophan synthase inhibitor(Eisai)

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	US	The University of Chicago	20 Jan 2020
Tuberculosis	Preclinical	US	Colorado State University	20 Jan 2020
Tuberculosis	Preclinical	US	The Broad Institute, Inc.	20 Jan 2020
Tuberculosis	Preclinical	JP	Eisai Co., Ltd.	20 Jan 2020

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