Adenosine Deaminase Inhibitors. Synthesis and Biological Evaluation of Putative Metabolites of (+)-erythro-9-(2S-Hydroxy-3R-nonyl)adenine

Vargeese, Chandra; Sarma, M. S. P.; Pragnacharyulu, P. V. P.; Abushanab, Elie; Li, Shih-Ying; Stoeckler, Johanna D.

doi:10.1021/jm00048a020

Cited by 17 publications

(15 citation statements)

References 19 publications

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“…To investigate this possibility, the presence of ADA was evaluated in culture medium from Ͼ90% viable cells. Thus, when the specific ADA1 inhibitor EHNA (100 M) [5,30] was added to the culture medium, ADA activity dropped from 8 to 6 U/liter, indicating that the ADA1 present in FCS is negligible, which fits with our preliminary results [12]. In supernatants of PBMCs cultured for 5 days, ADA activity was 13 Ϯ 1 U/liter, indicating that cell turnover contributes to this extracellular ADA.…”

Section: Incomplete Correlation Between Cell Surface Ada and Cd26 Expsupporting

confidence: 86%

Cytokines regulate membrane adenosine deaminase on human activated lymphocytes

Cordero

Salgado

Fernández-Alonso

et al. 2001

Journal of Leukocyte Biology

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CD26 is a lymphocyte marker that can anchor adenosine deaminase (ADA) on the T cell surface. We found that ADA is regulated by cytokines on the cell surface during T cell activation. By means of flow cytometry, immunofluorescence, and immunoblotting techniques, we found that interleukin (IL)-2 and IL-12 up-regulate ecto-ADA and CD26 expression. In clear contrast, IL-4 led to down-regulation of lymphocyte surface ADA without modifying the level of CD26. Moreover, neither circulating ADA transcription nor mRNA translation was regulated by cytokines. These results, along with absence of total-ADA modulation, the variable amount of ADA found in purified plasma membranes, and the different effect of Brefeldin A on the surface presence of ADA and CD26 indicated that cytokines regulate the translocation of ADA towards the cell surface through a mechanism not involving CD26. Ecto-ADA protected activated lymphocytes from the toxic effects of extracellular adenosine. Therefore, this cell surface ADA control might constitute part of the fine immunoregulatory mechanism of adenosine-mediated signaling through purinergic receptors in leukocytes.

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Section: Incomplete Correlation Between Cell Surface Ada and Cd26 Expsupporting

confidence: 86%

Cytokines regulate membrane adenosine deaminase on human activated lymphocytes

Cordero

Salgado

Fernández-Alonso

et al. 2001

Journal of Leukocyte Biology

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“…214 Chemically, EHNA is formed by adenine coupled in N9 to a chiral hydroxynonyl chain. 223 To reduce the¯exibility of the side chain (E/Z) double or triple bonds were introduced; only the Z-isomer of the double bond chain maintains an inhibitory activity comparable to EHNA itself. 215 Hydroxynonyl chain has been optimized by extensive SAR of N9-substituted adenines; 212,216,217 only a few modi®cations are tolerated.…”

Section: Ehna-like Compoundsmentioning

confidence: 99%

Adenosine deaminase: Functional implications and different classes of inhibitors

Cristalli¹,

Costanzi²,

Lambertucci³

et al. 2001

Med. Res. Rev.

289

250

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“…To block PDE II we utilized EHNA, a drug previously shown to inhibit adenosine deaminase and which selectively inhibits the activity of purified cGMP-stimulated PDE [2,29] and PDE II in isolated frog ventricular cells [19]. EHNA was used to block the cGMP pathway further downstream than PTIO and ODQ.…”

Section: Inhibition Of Pde II By Ehna Stimulates I Camentioning

confidence: 99%

Regulation of cardiac calcium current by NO and cGMP-modulating agents

Gallo

Malan

Bedendi

et al. 2000

Pflügers Arch - Eur J Physiol

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Several effects of nitric oxide (NO) on the control of L-type calcium current (ICa) and of calcium handling in cardiomyocytes have been described. Cardiomyocytes have been shown to express in different conditions all types of nitric oxide synthases (NOS), but the role of NO in the regulation of calcium current remains controversial. Previously, we have shown in guinea pig ventricular cells a stimulatory effect of NOS inhibitors on ICa. Here we investigate the intracellular mechanisms involved in the putative inhibitory role of NO on basal ICa in ventricular cells. The stimulatory effect of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) (1 mM) was present also in calcium transient measurements, but only after a preincubation with L-arginine (L-arg, 0.1 mM). The nitric oxide scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO, 0.5 mM) increased peak ICa in a similar manner to NOS inhibitors in whole-cell voltage-clamp experiments. Also ODQ (1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one, 0.1 mM), a specific inhibitor of a target of NO, the soluble guanylate cyclase, was able to stimulate ICa. The block of type II phosphodiesterase (cGMP-activated) by EHNA (erythro-9-[2-hydroxy-3-nonylladenine, 30 microM) exerted a similar effect on ICa as PTIO and ODQ. Carbachol (CCh, 1 microM) was able to revert the stimulatory effect on ICa observed with PTIO, ODQ, and EHNA. We propose that the increase of basal ICa in guinea pig cardiomyocytes previously observed with L-NMMA depends on the removal of a tonic NO inhibition. This increase of ICa is mimicked by blocking at different steps the cGMP-cascade activated by NO, suggesting a NO-guanylate cyclase mechanism in the basal control of ventricular calcium current.

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Adenosine Deaminase Inhibitors. Synthesis and Biological Evaluation of Putative Metabolites of (+)-erythro-9-(2S-Hydroxy-3R-nonyl)adenine

Cited by 17 publications

References 19 publications

Cytokines regulate membrane adenosine deaminase on human activated lymphocytes

Cytokines regulate membrane adenosine deaminase on human activated lymphocytes

Adenosine deaminase: Functional implications and different classes of inhibitors

Regulation of cardiac calcium current by NO and cGMP-modulating agents

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