Polyoxometalates with potent inhibitory activity at P2X receptors

P2X receptors are trimeric ligand-gated ion channels activated by ATP and permeable for cations such as Na⁺, K⁺ and Ca²⁺. Seven different subunits exist, assembled as homo- or heterotrimers of various stoichiometry.1 Polyoxometalates (POMs) are polynuclear metal-oxo anions of early transition metals in high oxidation states (e. g. W⁶⁺, Mo⁶⁺, V⁵⁺). This class of inorganic metal cluster compounds exhibits great variability with respect to shape, size, charge and composition.2 POMs bear several negative charges and in this respect resemble ATP, which binds to P2X receptors in its negatively charged state. We previously found that certain POMs can inhibit ATP-hydrolyzing ectonucleotidases.2-4 In the present study we investigated whether tungsten-containing POMs can interact with P2X receptors. A series of POMs was investigated for their ability to inhibit ATP-induced calcium influx in recombinant 1321N1 astrocytoma cells stably transfected with P2X receptor subtypes. Several POMs were found to be highly potent inhibitors of P2X receptors exhibiting low nanomolar potency. PEGylation of POMs to increase their metabolic stability was tolerated by the receptors. Structure-activity relationships at P2X receptor subtypes differed from those observed for ecto¬nucleotidases. The majority of POMs were found to be non-cytotoxic at pharmacologically active concentrations.

(1) Coddou, C., Yan, Z., Obsil, T., Huidobro-Toro, J.P., Stojilkovic, S.S. Activation and regulation of purinergic P2X receptor channels. Pharmacol Rev, 2011, 63:641-683
(2) Stephan, H., Kubeil, M., Emmerling, F., Müller, C.E. Polyoxometalates as versatile enzyme inhibitors. Eur. J. Inorg. Chem., 2013, 1585-1594
(3) Müller, C.E., Iqbal, J., Baqi, Y., Zimmermann, H., Röllich, A., Stephan, H. Polyoxometalates – a new class of potent ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitors. Bioorg Med Chem Lett, 2006, 16:5943-5947
(4) Lee, S., Fiene, A., Li, W., Hanck, T., Brylev, K.A., Fedorov, V.E., Lecka, J., Haider, A., Pietzsch, H.J., Zimmermann, H., Sévigny, J., Kortz, U., Stephan, H., Müller, C.E. Polyoxometalates – potent and selective ecto-nucleotidase inhibitors. Biochem Pharmacol, 2015, 93:171-181