Endogenous β‐Carbolines as Clonidine‐Displacing Substances

Robinson, Emma

doi:10.1196/annals.1304.018

Cited by 44 publications

(24 citation statements)

References 43 publications

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“…2a & b). This was consistent with the observation that most endogenous compounds exhibit a bell-shaped dose response relationship in normal cells when applied exogenously [20][21][22]. Cell proliferation response to S1P was also bell-shaped in the MCF7 cells with maximum stimulation obtained at 0.5 μM (Fig.…”

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confidence: 90%

Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer

et al. 2009

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Sphingosine-1-phosphate (S1P) is an important regulator of cancer development and progression. Its cellular concentration is controlled predominantly by sphingosine kinase (SK) and sphingosine-1-phosphate lyase (SPL). In the current study we showed that mRNA expressions for both SK and SPL were up-regulated throughout all four disease stages in human breast cancer patients. Exogenous administration of S1P produced a bell-shaped dose response for apoptosis in normal mammary gland MCF12A cells but a sigmoid-shaped apoptotic response in breast cancer MCF7 cells. Co-administration of S1P enhanced the cytotoxicity of anticancer drug docetaxel against MCF7 cells.

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confidence: 90%

Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer

et al. 2009

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“…The concentrations detected for norharmane in all 5 cultures (2-16 μg L −1 ) were obviously too low to be of an acute cytotoxicity. However, various pharmacological effects have been reported for norharmane in the past, such as the inhibition of several enzymes, e.g., of monoamine oxidase (Robinson et al 2003), of indoleamine 2,3-dioxygenase (Chiarugi et al 2000), of nitric oxide synthase (Chiarugi et al 2000;Connop et al 1995), and of acetylcholinesterase (Skup et al 1983), the increase of insulin secretion from isolated human islets of Langerhans (Cooper et al 2003), or the induction of apoptotic cell death in human neuroblastoma SH-SY5Y cells (Uezono et al 1991). Moreover, norharmane is characterized by a comutagenic activity (Totsuka et al 1998(Totsuka et al , 2002(Totsuka et al , 2004, and therefore the substance is in principle of toxicological interest and it is important to discover and evaluate all sources of such a potential risk factor.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic and non-cytotoxic exometabolites of the cyanobacterium Nostoc insulare

Volk

Mundt

2006

J Appl Phycol

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The isolation, identification and quantification of exometabolites from culture media of the cyanobacterium Nostoc insulare are described. Besides the known exometabolite 4,4′-dihydroxybiphenyl (I), two more compounds, the β-carboline 9H-pyrido(3,4-b) indole (norharmane, II) and N,N′-(4,5-dimethyl-1,2-phenylene)bis-acetamide (III), were discovered. Concentrations of all three compounds in media and biomass of five 250 L cultures of N. insulare were determined. Culture medium values for I ranged between 200 and 1,250 μg L −1 (1.1-6.7 μmol L −1 ), for III between 115 and 390 μg L −1 (0.5-1.8 μmol L −1 ), whereas concentrations of II were conspicuously lower (2-16 μg L −1 or 0.014 -0.094 μmol L −1 ). Amounts of III per volume of culture medium were about tenfold higher than in the biomass contained in an equal culture volume. This difference is an indication for an active excretion of III. Amounts of I and II in biomass and media were of no significant difference. In the neutral red uptake assay, I and II were found to be toxic against eukaryotic cells as follows: I was of considerable cytotoxicity in concentrations from 1,000 to 10 mg L −1 and of lower cytotoxicity (causing a 27 % decrease of cell viability) in a concentration of 1,000 μg L −1 , whereas II was merely of considerable cytotoxicity in concentrations from 1,000 to 100 mg L −1 . Because of the cytotoxicity of I and because of the many known pharmacological effects of II there is a possibility that a certain amount of risk to humans and livestock comes from cultures or even from biomassfree culture media of N. insulare. The natural function of the examined exometabolites is discussed.

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“…These ligands, tested for their ability to inhibit electrically evoked contractions in gunea-pig ileum, displayed agonist activity at a2 receptors below 300 nM whereas at higher concentrations all compounds showed a decreased activity. Based on these results it could not be ruled out a possible receptor modulation elicited by these compounds, that the previous reported molecular similarity study, Moreover, since I2-IBs modulated carbachol response at postjunctional level, for validating an useful ex vivo model to study I2 activity of compounds exerting mixed I2-a2 profile, we tested as reference compounds the endogenous I2-ligand, harmane, 18,19 and the putative I2 agonist 2BFI and antagonist BU224. 20,21 The inhibition activity of reference compounds harmane and 2BFI have been quantified and their effects were partially reversed by the I2 antagonist BU224.…”

Section: Discussionmentioning

confidence: 94%

“…17 All these ligands have been already studied in medicinal chemistry reports both for their physical and in vitro biological properties. 16,17 The validation of this method has been performed also testing the proposed endogenous ligand such as harmane, 18,19 and known I2 agonist and antagonist, 2BFI and BU224, respectively. 20,21 Materials and Methods…”

Section: Introductionmentioning

confidence: 99%

Guinea-pig ileum as ex vivo model useful to characterize ligands displaying Imidazoline I2 and Adrenergic alpha2 mixed activity: a preliminary study

et al. 2013

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The lack of an effective analgesic treatment makes pain a clinical challenge and the need of a novel approach to identify new agents is urgent. In this scenario I2-ligands can be considered an alternative strategy in pain therapy. The development of an ex vivo model useful for the evaluation of functional activities at both a2 and I2-IBs (imidazoline binding sites) is an important task in pharmacological sciences since several I2 ligands display activity also towards a receptors. The present study aims to develop an ex vivo model for estimating the activity of I2-IBs ligands in a biological sample where a1 and a2 adrenergic receptors are present. For this purpose the imidalzoline endogenous ligand, harmane, reference compounds, 2BFI and BU224, and imidazoline derivatives 1-3 have been selected taking into account their in vitro activity towards IBs and adrenergic receptors. All compounds have been tested ex vivo in guinea pig-ileum where a2A-ARs are prejunctionally and I2-IBS postjunctionally localized. Adrenergic component has been identified by the studying the interference of compounds on the electricallyevoked contraction while I2-IBs activity by testing the ability of compounds to inhibit the carbachol-evoked contractions in the presence of prazosin to mask the a1 adrenoceptors. Compounds 1 and 2 were found I2-IBs antagonists (pIC50=4.2 and 4.0, respectively) whereas compound 3 was I2-IBs agonist (EC50=0.38 mM); All ligands were a2 adrenergic agonists. This paper suggests guinea-pig ileum as the first ex vivo approach for establishing both the intrinsic activity of I2-IBs ligands and the physiological correlation between IBs and adrenergic system.

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Endogenous β‐Carbolines as Clonidine‐Displacing Substances

Cited by 44 publications

References 43 publications

Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer

Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer

Cytotoxic and non-cytotoxic exometabolites of the cyanobacterium Nostoc insulare

Guinea-pig ileum as ex vivo model useful to characterize ligands displaying Imidazoline I2 and Adrenergic alpha2 mixed activity: a preliminary study

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