Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases)

Abstract

Reactive blue 2 (RB-2) had been characterized as a relatively potent ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) inhibitor with some selectivity for NTPDase3. In search for the pharmacophore and to analyze structure-activity relationships we synthesized a series of truncated derivatives and analogs of RB-2, including 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinones, 1-amino-2-methyl-4-arylaminoanthraquinones, 1-amino-4-bromoanthraquinone 2-sulfonic acid esters and sulfonamides, and bis-(1-amino-4-bromoanthraquinone) sulfonamides, and investigated them in preparations of rat NTPDase1, 2, and 3 using a capillary electrophoresis assay. Several 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinone derivatives inhibited E-NTPDases in a concentration-dependent manner. The 2-sulfonate group was found to be required for inhibitory activity, since 2-methyl-substituted derivatives were inactive.

Structure–Activity Relationships of a Novel Group of Large‐Conductance Ca2+‐Activated K+ (BK) Channel Modulators: The GoSlo‐SR Family

“…[16][17][18][19][20] However we do not believe that the BK channel agonist activity demonstrated here results from an interaction with purinoceptors or by inhibition of either eN or E-NTPDase, for a number of reasons. We have previously shown that suramin, [11] a non-specific purinoceptor antagonist and ecto-ATPase inhibitor has no effect on BK channels when applied (at concentrations up to 1 mM) to the cytosolic surface of BK channels in bladder smooth muscle.…”

“…The effect of different substituents on the phenyl ring in the N 4 -position was investigated (see Table 1). Eight of the analogues (marked with an asterisk in Table 1) have been reported previously to act as purinoceptor antagonists, [16][17][18] ecto-5′-nucleotidease (eN) inhibitors, [19] or ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) inhibitors, [20] but the remainder of the analogues were novel. When we examined the effects of these molecules on BK channels, we found that a significant number of the compounds were efficacious BK channel activators and shifted the activation V1/2 in excess of -80 mV (see Table 1).…”

Crystallographic Evidence for a Domain Motion in Rat Nucleoside Triphosphate Diphosphohydrolase (NTPDase) 1

“…Specific NTPDase1 inhibitors would constitute a potential clinical therapeutic in the treatment of cancer and immune deficiency diseases. [30][31][32][33][34] Despite considerable effort, [34][35][36] nanomolar inhibitors with high subtype specificity are not yet available. On the other hand, increasing NTPDase activity would be desirable in the case of occlusive vascular diseases, vascular inflammation and inflammatory autoimmune diseases.…”

Evidence for the existence of pyrimidinergic transmission in rat brain

“…To identify and quantify these nucleotides in brain ECF we have developed a new method which involves including in the dialysate medium PSB069, a non-selective nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitor that inhibits rat NTPDases 1, 2 and 3 with similar potencies (Baqi et al, 2009). Addition of PSB069 into the perfusion fluid enabled us to detect uridine nucleotides in the extracellular fluid reliably.…”

“…The dialysis probe was perfused at a rate of 2 ml/min with artificial cerebrospinal fluid (CSF; pH ¼ 7.4) of the following composition: 148 mM NaCl, 3.0 mM KCl, 1.4 mM CaCl 2 , 0.8 mM MgCl 2 , 1.3 mM NaH 2 PO 4 , 0.2 mM Na 2 HPO 4 . The artificial CSF also contained PSB069 (Tocris Bioscience, Bristol, UK), a non-selective nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitor, which reportedly inhibits rat NTPDases 1, 2 and 3 with similar potencies (Baqi et al, 2009). Addition of PSB069 to the perfusion fluid protected extracellular uridine nucleotides from hydrolysis, and enabled us to measure these nucleotides in extracellular fluid by in vivo microdialysis technique.…”