PPNDS

PPNDS is an agonist, not an antagonist, for the ATP receptor of Paramecium.[Pubmed:12502783]

J Exp Biol. 2003 Feb;206(Pt 3):627-36.

Paramecium represents a simple, eukaryotic model system to study the cellular effects of some neuroactive drugs. They respond to the agonist beta,gamma-methylene ATP with a transient depolarizing receptor potential, Ca(2+)-based action potentials and repetitive bouts of forward and backward swimming called 'avoiding reactions' (AR). In vivo [(32)P]ATP binding assays showed saturable [(32)P]ATP binding with an apparent K(d) of approximately 23 nmol l(-1). Prolonged (15 min) exposure to 25 micro mol l(-1) beta,gamma-methylene ATP caused behavioral adaptation and losses of AR, ATP receptor potentials and [(32)P]ATP binding. While screening various ATP receptor inhibitors, we found that the P2X1 'antagonist' pyridoxal-phosphate naphthylazo-nitro-disulfate (PPNDS) is actually an agonist, producing the same responses as beta,gamma-methylene ATP. [(32)P]ATP binding assays suggest that both agonists may bind to the same site as [(32)P]ATP. Cross-adaptation is also seen between PPNDS and beta,gamma-methylene ATP in terms of losses in AR, depolarizing receptor potentials and [(32)P]ATP binding. We conclude that the inhibition caused by PPNDS in Paramecium is due to agonist-induced desensitization. Either this represents a unique new class of ATP receptors, in which PPNDS is an agonist instead of an antagonist, or PPNDS (and other drugs like it) may actually be an agonist in many other cell types in which prolonged exposure is necessary for inhibition.

The novel pyridoxal-5'-phosphate derivative PPNDS potently antagonizes activation of P2X(1) receptors.[Pubmed:10650184]

Eur J Pharmacol. 2000 Jan 17;387(3):R19-21.

Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonat e) (PPNDS) potently antagonized P2X(1) receptor-mediated responses in rat vas deferens (pK(B)=7.43) and Xenopus laevis oocytes (pIC(50)=7. 84). It showed lower (up to 20,000-fold) inhibitory potency on ecto-nucleotidase in Xenopus oocytes and on P2Y(1) receptors in guinea-pig ileum (pA(2)=6.13). PPNDS did not interact with alpha(1A)-adrenoceptors, adenosine A(1) and A(2B), histamine H(1) and muscarinic M(3) receptors. Thus, PPNDS is a novel, specific P2 receptor antagonist and represents the pyridoxal-5'-phosphate derivative with the highest potency at P2X(1) receptors.

PPNDS inhibits murine Norovirus RNA-dependent RNA-polymerase mimicking two RNA stacking bases.[Pubmed:24657439]

FEBS Lett. 2014 May 2;588(9):1720-5.

Norovirus (NV) is a major cause of gastroenteritis worldwide. Antivirals against such important pathogens are on demand. Among the viral proteins that orchestrate viral replication, RNA-dependent-RNA-polymerase (RdRp) is a promising drug development target. From an in silico-docking search focused on the RdRp active site, we selected the compound PPNDS, which showed low micromolar IC50vs. murine NV-RdRp in vitro. We report the crystal structure of the murine NV-RdRp/PPNDS complex showing that two molecules of the inhibitor bind in antiparallel stacking interaction, properly oriented to block exit of the newly synthesized RNA. Such inhibitor-binding mode mimics two stacked nucleotide-bases of the RdRp/ssRNA complex.

Divergent effects of the purinoceptor antagonists suramin and pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.[Pubmed:15448189]

Mol Pharmacol. 2004 Dec;66(6):1738-47.

Suramin is a large naphthyl-polysulfonate compound that inhibits an array of receptors and enzymes, and it has also been reported to block currents mediated by glutamate receptors. This study shows that suramin and several structurally related compounds [8,8'-[carbonylbis(imino-3,1-phenylenecarbonylamino)]bis-(1,3,5-naphthalenetrisul fonic acid), 6Na (NF023), 8,8'-(carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino))bi s-1,3,5-naphthalenetrisulfonic acid, Na (NF279), and 4,4',4'',4'''-[carbonyl-bis[imino-5,1,3-benzenetriyl-bis-(carbonylimino)]]tetraki s-benzene-1,3-disulfonic acid, 8Na (NF449)] reduce binding of [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and [3H]fluorowillardiine to rat brain membranes and homomeric GluR1-4 receptors, with IC50 values in the range of 5 to 180 microM. Inhibition often was less than complete at saturating drug concentrations and thus seems to be noncompetitive in nature. Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) is a potent antagonist of purinoceptors that shares some structural elements with suramin yet is smaller than the latter. PPNDS also had potent effects on AMPA receptors (EC50 value of 4 microM) but of a kind not seen with the other compounds in that it increased binding affinity for radioagonists severalfold. In addition, PPNDS slowed association and dissociation rates more than 10 times. In physiological experiments with GluR2 receptors, PPNDS at 50 microM reduced the peak current by 30 to 50% but had only small effects on other waveform aspects such desensitization and steady-state currents. This pattern of effects differentiates PPNDS from other compounds such as thiocyanate and up-modulators, which increase agonist binding by enhancing desensitization or slowing deactivation, respectively. Receptor model simulations indicate that most effects can be accounted for by assuming that PPNDS slows agonist binding/unbinding and stabilizes the bound-closed state of the receptor. By extension, suramin is proposed to stabilize the unbound state and thereby to reduce affinity for agonists. These drugs thus act through a novel type of noncompetitive antagonism.