Novel inhibitors of the sodium–calcium exchanger: benzene ring analogues of N-guanidino substituted amiloride derivatives

Rogister, F.; Laeckmann, Didier; Plasman, Pierre-Olivier; Eylen, Françoise Van; Ghyoot, Marianne; Maggetto, Carine; Liégeois, Jean-François; Géczy, Joseph; Herchuelz, André; Delarge, J.

doi:10.1016/s0223-5234(01)01247-8

Cited by 38 publications

(30 citation statements)

References 36 publications

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“…As we anticipated, compound 26 increased the activity dramatically, showing the strong activity with an IC 30 value of 0.02 mM. Its activity was almost same as previously reported compound 9 11) having the 3,4-dihydro-2(1H)-quinazolinone skeleton.…”

Section: Pharmacological Results and Discussionsupporting

confidence: 87%

“…As a peptidic inhibitor, Val-Met-Arg-Phe-NH 2 (1) with IC 50 value of 1.5 mM has been reported, which is a non-selective inhibitor. 10) As a non-peptidic inhibitor, aroylguanidine derivative (2) 11) with IC 50 value of 3.4 mM has been reported which is a modified amiloride derivative as is dimethylamiloride (3). 12) Furthermore, KB-R7943 (4), 13,14) SEA0400 (5), 15,16) benzyloxyphenyl derivative (6) 17) and SN-6 (7) 18) have been reported.…”

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confidence: 99%

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Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

Hasegawa¹,

Muraoka²,

Ohmori³

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Section: Pharmacological Results and Discussionsupporting

confidence: 87%

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confidence: 99%

Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

Hasegawa¹,

Muraoka²,

Ohmori³

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The Ca 21 signal elicited in these cells by Na 1 -free perfusion was comparable in terms of magnitude and duration. The increase was blocked by the amiloride derivative CB-DMB [35,37]; it was not sensitive to the L-type Ca 21 -channel blocker nimodipine [40]; and it was markedly increased by blocking SERCA with thapsigargin [28,35]. The characteristics of Ca 21 signals in monocytes and macrophages resemble those found in other NCX-expressing cells such as primary neuronal cells [50] and BHK cells stably transfected with NCX1 and NCX3 [35].…”

Section: Discussionmentioning

confidence: 89%

“…To verify that the Ca 21 signal induced by the Na 1 -free medium in HLM and monocytes was only due to the NCX activity, cells were preincubated (371C, 1 h) with the amiloride derivative 5-(N-4-chlorobenzyl)-20,40-dimethylbenzamil (CB-DMB) (10 mM) -a pan inhibitor of all three NCX isoforms [35,37] -before exposure to the Na 1 -free medium. CB-DMB completely blocked the Ca 21 influx elicited by Na 1 -free perfusion in HLM ( Fig.…”

Section: Effect Of Cb-dmb On the [Ca 21 ] I Increase Induced By Na 1 mentioning

confidence: 99%

Expression and function of Na⁺/Ca²⁺ exchangers 1 and 3 in human macrophages and monocytes

et al. 2009

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The Na 1 /Ca 21 exchanger (NCX) is a membrane transporter that can switch Na 1 and Ca 21 in either direction to maintain the homeostasis of intracellular Ca 21 . Three isoforms (NCX1, NCX2, and NCX3) have been characterized in excitable cells, e.g. neurons and muscle cells. We examined the expression of these NCX isoforms in primary human lung macrophages (HLM) and blood monocytes. NCX1 and NCX3, but not NCX2, are expressed in HLM and monocytes at both mRNA and protein levels. Na 1 -free medium induced a significant increase in intracellular calcium concentration ([Ca 21 ] i ) in both cell types. This response was completely abolished by the NCX inhibitor 5-(N-4-chlorobenzyl)-20,40-dimethylbenzamil (CB-DMB). Moreover, inhibition of NCX activity during Ca 21 -signaling induced by histamine caused a delay in restoring baseline [Ca 21 ] i . Na 1 -free medium induced TNF-a expression and release in HLM comparable to that caused by LPS. TNF-a release induced by Na 1 -free medium was blocked by CB-DMB and greatly reduced by RNAi-mediated knockdown of NCX1. These results indicate that human macrophages and monocytes express NCX1 and NCX3 that operate in a bidirectional manner to restore [Ca 21 ] i , to generate Ca 21 -signals, and to induce TNF-a production. Therefore, NCX may contribute to regulate Ca 21 homeostasis and proinflammatory functions in human macrophages and monocytes.Key words: Ca 21 -signaling . Macrophages . Monocytes . Na 1 /Ca 21 exchanger IntroductionThe Na 1 /Ca 21 exchanger (NCX) is a plasma membrane protein involved in the homeostasis of intracellular Ca 21 [1]. NCX is a bidirectional ion transporter that catalyzes the exchange of Na 1 and Ca 21 depending on their electrochemical gradients [2]. Under physiological conditions, NCX's primary role is to extrude Ca 21 from cells using the Na 1 gradient across the cell membrane (forward mode of operation) [3]. However, in some cases it can contribute to the Ca 21 influx into the cells by working in the reverse mode (i.e. coupling Ca 21 influx with Na 1 efflux) [4][5][6].Three isoforms of NCX, NCX1, NCX2, and NCX3 have been cloned in mammals, outlining a multigene family whose members share a similar molecular structure [7]. NCX is modeled with nine transmembrane segments involved in ion transport and a long central cytoplasmic loop that has regulatory functions [8]. However, truncated forms lacking certain transmembrane segments, but still possessing NCX activity, have also been Eur. J. Immunol. 2009. 39: 1405-1418 DOI 10.1002 Leukocyte signaling 1405 described as the result of alternative splicing of the three genes [9][10][11]. NCX1 is largely predominant in mammalian tissues such as heart, brain, and kidney while the expression of NCX2 and NCX3 appears to be limited to the brain and skeletal muscle [7]. NCX is a key element regulating intracellular Ca 21 concentrations ([Ca 21 ] i ) in many excitable cells, including myocardiocytes, retinal rod photoreceptors, smooth muscle cells, and neurons [3]. Non-excitable cells such as renal epithelial ce...

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“…These have motivated the development of many reagents for their synthesis and various methods to achieve guanylation by nucleophilic addition of an amine to a cyanamide. 4) The guanidine derivatives exhibited diverse biological and pharmacological activities such as neuronal Na + and Ca 2+ channel blockers, 5) glutamate release inhibitors, anti-ischemic agents, 6) anti-seizure agents, 7) aderenergic neuron-blocking agents, 8) human immunodeficiency virus-1 (HIV-1) protease inhibitors, 9) K + /ATP channel openers, nitric oxide (NO) synthase inhibitors, influenza neuraminidase inhibitors, 10) cardiotonic agents, 11) and histamine H 3 receptor antagonists. 12) Therefore, the guanidine functional group is an attractive pharmacophore for the development of novel drugs against tumors, hypertension, glaucoma, and inflammation.…”

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confidence: 99%

Synthesis of Novel Phosphorylated Guanidine Derivatives from Cyanamide and Their Anti-inflammatory Activity

Katla

Syed

Kuruva

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of novel guanidine derivatives were synthesized in three steps and their anti-inflammatory activities in vitro and in vivo evaluated. 2-Aminopyridin-3-ol (1) was reacted with thiophosphoryl chloride (2) to give a monochloride (3). It was further reacted with cyanamide to afford the corresponding cyanamine (4), which was subsequently reacted with different heterocyclic amines to form the title compounds (5a-l). The substituent in the guanidine function affected the potency of anti-inflammatory activity. The compounds having benzothiazole, fluorophenyl, and piperazinyl moieties enhanced the anti-inflammatory activity.Key words phosphorylated guanidine; 2-aminopyridin-3-ol; anti-inflammatory activity Compounds containing a guanidine functional group exhibit many biological, chemical and medicinal applications.

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Novel inhibitors of the sodium–calcium exchanger: benzene ring analogues of N-guanidino substituted amiloride derivatives

Cited by 38 publications

References 36 publications

Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

Expression and function of Na⁺/Ca²⁺ exchangers 1 and 3 in human macrophages and monocytes

Synthesis of Novel Phosphorylated Guanidine Derivatives from Cyanamide and Their Anti-inflammatory Activity

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Novel inhibitors of the sodium–calcium exchanger: benzene ring analogues of N-guanidino substituted amiloride derivatives

Cited by 38 publications

References 36 publications

Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

Design, Synthesis, and Structure-Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor

Expression and function of Na+/Ca2+ exchangers 1 and 3 in human macrophages and monocytes

Synthesis of Novel Phosphorylated Guanidine Derivatives from Cyanamide and Their Anti-inflammatory Activity

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Expression and function of Na⁺/Ca²⁺ exchangers 1 and 3 in human macrophages and monocytes