Potent, Selective Tetrahydro-β-carboline Antagonists of the Serotonin 2B (5HT<sub>2B</sub>) Contractile Receptor in the Rat Stomach Fundus

Audia, James E.; Evrard, Deborah A.; Murdoch, Gwyn R.; Droste, James J.; Nissen, Jeffrey S.; Schenck, K. W.; Fludzinski, Pawel; Lucaites, Virginia L.; Nelson, David L.; Cohen, Marlene L.

doi:10.1021/jm960062t

Cited by 126 publications

(74 citation statements)

References 30 publications

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“…LY266070 (1 nM), a selective antagonist of the 5-HT2B receptor (24), reduced by 52% the AA release measured at day 4, whereas it abolished PLA2 activation at day 2 by nearly 100% (Fig. 3).…”

Section: The Activation Of 5-ht2b Receptor Subtypes Increasesmentioning

confidence: 95%

Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line

Tournois¹,

Mutel²,

Manivet³

et al. 1998

Journal of Biological Chemistry

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Section: The Activation Of 5-ht2b Receptor Subtypes Increasesmentioning

confidence: 95%

Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line

Tournois¹,

Mutel²,

Manivet³

et al. 1998

Journal of Biological Chemistry

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“…8,[13][14][15][16] Therefore, in this study, we used these agents to investigate the involvement of 5-HT 2 receptor subtypes and their intracellular signal transduction pathways in 5-HT-induced hepatocyte DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.…”

mentioning

confidence: 99%

Signal Transduction Mechanism for Serotonin 5-HT<sub>2B</sub> Receptor-Mediated DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes

Naito

Tanaka

Mitsuhashi

et al. 2016

Biological & Pharmaceutical Bulletin

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Key words serotonin (5-hydroxytryptamine); signal transduction; DNA synthesis; proliferation (cultured hepatocyte); transforming growth factor-α Although adult rat hepatocytes rarely undergo cell division under normal physiological conditions, due to the ensuing regenerative response to recruit mature hepatocytes into the cell cycle in vivo after 70% partial hepatectomy, a phenomenon known as liver regeneration, 1,2) they do remain capable of proliferation. Among the numerous growth-promoting factors that pertain to liver regeneration, platelet-derived serotonin (5-hydroxytryptamine; 5-HT) is reportedly directly involved. 3-7)5-HT is not only a neurotransmitter, but also a kind of hormone with various extraneural functions. 5-HT mediates a diverse array of responses-including platelet aggregation, vascular constriction, and cell proliferation-by interacting with 5-HT receptor subtypes in mammals.8) Seven receptor classes including 14 subtypes of 5-HT receptors have been identified to date, reflecting the diversity of 5-HT actions. With the exception of the 5-HT 3 receptors, which are ligand-gated ion channels, all known 5-HT receptors are G-protein-coupled receptors that are positively linked to phosphatidylinositol turnover or cyclic AMP production and are further linked to a variety of downstream pathways. [9][10][11] In the presence of epidermal growth factor (EGF) and insulin, 5-HT has been shown to cause a dose-dependent increase in DNA synthesis in primary cultures of rat hepatocytes, suggesting that it is also a co-mitogen.12) In addition, interaction has also been seen between 5-HT and various hematological factors such as hepatocyte growth factor (HGF) and platelet-derived growth factor (PDGF). Although 5-HT has been shown to play significant roles in the stimulation and acceleration of hepatocyte proliferation, 6) few studies have been conducted on the possible involvement of 5-HT 2 receptor subtypes and their intracellular signal transduction pathways in 5-HT-induced hepatocyte DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.Some recently identified selective 5-HT receptor agonists and antagonists have shown promise as useful tools for differentiating between closely related 5-HT 2 receptor subtypes. 8,[13][14][15][16] Therefore, in this study, we used these agents to investigate the involvement of 5-HT 2 receptor subtypes and their intracellular signal transduction pathways in 5-HT-induced hepatocyte DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. MATERIALS AND METHODSAnimals Male Wistar rats (weight range, 200-220 g) were purchased from Tokyo Experimental Animal Co. (Tokyo, Japan) and adapted to a light-, humidity-and temperature-controlled room over a minimum 3-d period prior to the start of the experiments. All rats were fed with a standard laboratory diet and given tap water ad libitum. All rats used in this study were given human care in compliance with Guiding Principles for the Care and Use of Laboratory Animals approved by The Japanes...

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“…1) Previous investigations focused on the effects of b-carboline alkoloids on the central nervous system (CNS). [2][3][4][5][6][7][8][9] Recent reports [10][11][12][13][14][15][16][17] have pointed out b-carbolines as a class of potential antitumor agents, which was discovered to function their antitumor activity through multiple mechanisms, such as intercalating into DNA, 11,18) inhibiting topoisomerase I and II, 13) CDK, [19][20][21] MAPKAP-K2, 22) MK-2, 23) PLK1 24) and kinesin Eg5. 25) Recently, our group investigations [26][27][28][29][30][31] on the synthesis of a variety of b-carboline derivatives and the evaluation of their antitumor activities unraveled that b-carbolines had potent antitumor activities and the activities were correlated to both the planarity of the molecule and the presence of the ring substituents.…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel .BETA.-Carbolines as Potent Cytotoxic and DNA Intercalating Agents

Chen

Cao

Shi

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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901Regular Article b-Carboline alkaloids represent a large number of naturally and synthetic indole alkaloids associated with a broad spectrum of biochemical effects and pharmaceutical properties.1) Previous investigations focused on the effects of b-carboline alkoloids on the central nervous system (CNS). 2-9)Recent reports [10][11][12][13][14][15][16][17] have pointed out b-carbolines as a class of potential antitumor agents, which was discovered to function their antitumor activity through multiple mechanisms, such as intercalating into DNA, 11,18) and kinesin Eg5. 25)Recently, our group investigations 26-31) on the synthesis of a variety of b-carboline derivatives and the evaluation of their antitumor activities unraveled that b-carbolines had potent antitumor activities and the activities were correlated to both the planarity of the molecule and the presence of the ring substituents. Structure-activity relationships (SARs) analysis suggested that the introduction of appropriate substituents into position-2, 3 and 9 played a vital role in determining their antitumor effects, and the n-butyl, benzyl or phenylpropyl substituents at position-9 was suitable pharmacophoric group giving rise to some potent antitumor agents.In continuing search for novel and effective antitumor agents, we designed and synthesized a series of water-soluble b-carbolines bearing a flexible alkylamino side chain at position-3 and a alkyl or arylated alkyl substituent at position-9, respectively. The selective introduction of a methyl, n-butyl, benzyl, 4-fluorobenzyl and phenylpropyl substituents into position-9 of b-carboline nucleus was based on the previous SARs analysis results, and the design of the amino substituents was limited to diethylaminoethylamino, dimethylaminopropylamino diethylaminopropylamino and diethylaminobutylamino group. The purpose of this study was to investigate effect of the flexible amino side chain moiety on the antitumor activity, with the ultimate aim of developing novel antitumor b-carbolines with improved water solubility and bioavailability. ChemistryThe synthetic routes of novel b-carbolines 1a, 2a-d, 3a-d, 4a-d, 5a-d and 6a-d are outlined in Chart 1. 1-Methyl-b-carboline-3-carboxaldehydes 1-6 were prepared from the L-tryptophan via six steps including the Pictet-Spengler condensation, esterification, aromatization, N-alkylation or N-arylation, reduction and oxidation as previously described. [26][27][28] The reaction of compounds 1-6 with the corresponding diamines to form schiff bases took place readily at room temperature in good yield. The crude schiff bases without further purification were directly reduced with NaBH 3 CN in anhydrous methanol to give the target b-carbolines 1a, 2a-d, 3a-d, 4a-d, 5a-d and 6a-d (Table 1) in 40-78% yield. The chemical structures of all the synthesized compounds were characterized by MS, IR, 1 H-NMR, and 13 C-NMR spectra. Results and DiscussionCytotoxic Activity in Vitro The cytotoxic potential of all newly synthesized b-carbolines was evaluated in vitro against a pa...

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Potent, Selective Tetrahydro-β-carboline Antagonists of the Serotonin 2B (5HT_2B) Contractile Receptor in the Rat Stomach Fundus

Cited by 126 publications

References 30 publications

Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line

Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line

Signal Transduction Mechanism for Serotonin 5-HT<sub>2B</sub> Receptor-Mediated DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes

Synthesis and Biological Evaluation of Novel .BETA.-Carbolines as Potent Cytotoxic and DNA Intercalating Agents

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Potent, Selective Tetrahydro-β-carboline Antagonists of the Serotonin 2B (5HT2B) Contractile Receptor in the Rat Stomach Fundus

Cited by 126 publications

References 30 publications

Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line

Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line

Signal Transduction Mechanism for Serotonin 5-HT<sub>2B</sub> Receptor-Mediated DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes

Synthesis and Biological Evaluation of Novel .BETA.-Carbolines as Potent Cytotoxic and DNA Intercalating Agents

Contact Info

Product

Resources

About

Potent, Selective Tetrahydro-β-carboline Antagonists of the Serotonin 2B (5HT_2B) Contractile Receptor in the Rat Stomach Fundus