作者: 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.

2023-02-01·Psychopharmacology

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

Article

作者: 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.

2020-08-01·Progress in Neuro-Psychopharmacology and Biological Psychiatry2区 · 医学

Insights into serotonergic and antioxidant mechanisms involved in antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran in mice

2区 · 医学

Article

作者: Alves, Diego ; Spohr, Luiza ; Gonçalves Alves, Amália ; Dos Santos Neto, José Sebastião ; Brüning, César Augusto ; Pereira Soares, Mayara Sandrielly ; Folharini Bortolatto, Cristiani ; Carraro Júnior, Luiz Roberto ; Gall, Jéssica Iara ; da Silva Teixeira Rech, Taís ; Spanevello, Rosélia Maria

Monoaminergic and oxidative dysfunctions have been reported to play a role in depression. The present study investigated the antioxidant potential as well as the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in male Swiss mice. Time and dose-response curves were analyzed with the forced swim (FST) and tail suspension (TST) tests, in which SeBZF1 elicited antidepressant-like effects. Serotonergic mechanisms were investigated in the TST. The pre-administration of WAY100635 (selective 5-HT_1A receptor antagonist, 0.1 mg/kg, subcutaneous route), ketanserin (5-HT_2A/2C receptor antagonist, 1 mg/kg, intraperitoneal route, i.p.), and chlorophenylalaninemethyl ester (p-CPA) (selective tryptophan hydroxylase inhibitor, 100 mg/kg, i.p., for 4 days), but not of ondansetron (selective 5-HT₃ receptor antagonist, 1 mg/kg, i.p.), abolished the antidepressant-like action of SeBZF1 (50 mg/kg, intragastric route, i.g.). Co-administration of sub-effective doses of SeBZF1 (1 mg/kg, i.g.) and fluoxetine (5 mg/kg, i.p., selective serotonin reuptake inhibitor) was effective in producing anti-immobility effects in the TST, revealing a synergistic effect. Besides, p-CPA induced hippocampal oxidative stress, characterized by a reduction of total thiols and lipoperoxidation, which was reversed by SeBZF1 (50 mg/kg). The in vitro screening of the antioxidant action of SeBZF1 in brain tissue reinforced these results. Lastly, SeBZF1 did not cause systemic toxicity at a high dose (300 mg/kg). In summary, the present study demonstrated that SeBZF1 exerted antidepressant-like action in male mice which appears to be mediated by the serotonergic system. Moreover, SeBZF1 elicited in vitro antioxidant action in brain tissue, attenuated the hippocampal oxidative damage induced by 5-HT depletion in mice and showed no toxic signs.

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适应症	最高研发状态	国家/地区	公司	日期
结核	临床前	美国	The University of Chicago	2020-01-20
结核	临床前	美国	Colorado State University	2020-01-20
结核	临床前	美国	The Broad Institute, Inc.	2020-01-20
结核	临床前	日本	Eisai Co., Ltd.	2020-01-20