POM 1

New eco-friendly 1-alkyl-3-(4-phenoxybutyl) imidazolium-based ionic liquids derivatives: a green ultrasound-assisted synthesis, characterization, antibacterial activity and POM analyses.[Pubmed:25153856]

Molecules. 2014 Aug 7;19(8):11741-59.

In view of the emerging importance of the ILs as "green" materials with wide applications and our general interests in green processes, a series of a twenty five new 1-alkyl-3-(4-phenoxybutyl) imidazolium-based ionic liquids (ILs) derivatives is synthesized using a facile and green ultrasound-assisted procedure. Their structures were characterized by FT-IR, 1H-NMR, 13C-NMR, 11B, 19F, 31P, and mass spectrometry. Antimicrobial screens of some selected ILs were conducted against a panel of Gram-positive and Gram-negative bacteria. The antimicrobial activity of each compound was measured by determination of the minimal inhibitory concentration (MIC) yielding very interesting and promising results. Their antibacterial activities are reported, and, on the basis of the experimental and virtual POM screening data available, attempt is also made to elucidate the structure activity relationship.

Biochemical characterization of the POM-1 metallo-beta-lactamase from Pseudomonas otitidis.[Pubmed:25512428]

Antimicrob Agents Chemother. 2015 Mar;59(3):1755-8.

The POM-1 metallo-beta-lactamase is a subclass B3 resident enzyme produced by Pseudomonas otitidis, a pathogen causing otic infections. The enzyme was overproduced in Escherichia coli BL21(DE3), purified by chromatography, and subjected to structural and functional analysis. The purified POM-1 is a tetrameric enzyme of broad substrate specificity with higher catalytic activities with penicillins and carbapenems than with cephalosporins.

Ionotropic glutamate receptor GluA4 and T-type calcium channel Cav 3.1 subunits control key aspects of synaptic transmission at the mouse L5B-POm giant synapse.[Pubmed:26390982]

Eur J Neurosci. 2015 Dec;42(12):3033-44.

The properties and molecular determinants of synaptic transmission at giant synapses connecting layer 5B (L5B) neurons of the somatosensory cortex (S1) with relay neurons of the posteriomedial nucleus (POm) of the thalamus have not been investigated in mice. We addressed this by using direct electrical stimulation of fluorescently labelled single corticothalamic terminals combined with molecular perturbations and whole-cell recordings from POm relay neurons. Consistent with their function as drivers, we found large-amplitude excitatory postsynaptic currents (EPSCs) and multiple postsynaptic action potentials triggered by a single presynaptic action potential. To study the molecular basis of these two features, ionotropic glutamate receptors and low voltage-gated T-type calcium channels were probed by virus-mediated genetic perturbation. Loss of GluA4 almost abolished the EPSC amplitude, strongly delaying the onset of action potential generation, but maintaining the number of action potentials generated per presynaptic action potential. In contrast, knockdown of the Cav 3.1 subunit abrogated the driver function of the synapse at a typical resting membrane potential of -70 mV. However, when depolarizing the membrane potential to -60 mV, the synapse relayed single action potentials. Hence, GluA4 subunits are required to produce an EPSC sufficiently large to trigger postsynaptic action potentials within a defined time window after the presynaptic action potential, while Cav 3.1 expression is essential to establish the driver function of L5B-POm synapses at hyperpolarized membrane potentials.

The novel NTPDase inhibitor sodium polyoxotungstate (POM-1) inhibits ATP breakdown but also blocks central synaptic transmission, an action independent of NTPDase inhibition.[Pubmed:18768144]

Neuropharmacology. 2008 Dec;55(7):1251-8.

Understanding the mechanisms and properties of purinergic signalling would be greatly assisted by the discovery of subtype selective and potent inhibitors of the NTPDase enzymes, which metabolise nucleotides such as ATP and ADP in the extracellular space. Currently ARL 67156 is the best available NTPDase inhibitor, but its relatively poor efficacy means that negative results are difficult to interpret. POM-1 (sodium polyoxotungstate) is a novel NTPDase inhibitor, which has shown promising results with the inhibition of recombinant NTPDases 1, 2 and 3. We have tested the effectiveness and physiological effects of POM-1 with cerebellar and hippocampal slices. Using the malachite green phosphate assay, HPLC and biosensor measurements we have found that POM-1 is more effective at blocking ATP breakdown in cerebellar slices than ARL 67156. The site of inhibition is at the first step of the breakdown cascade (conversion of ATP to ADP) and the effects of POM-1 appear readily reversible. However, POM-1 has multiple effects on synaptic transmission. At the cerebellar parallel fibre-Purkinje cell (PF) synapse POM-1 produced a long lasting inhibition of transmission, which was preceded in a minority of synapses by a transient increase in PF excitatory postsynaptic potential (EPSP) amplitude (approximately 20%). This increase in PF EPSP amplitude appears to result from a reduction in the tonic activation of presynaptic A1 receptors, consistent with POM-1 preventing the breakdown of ATP to adenosine. The reduction in PF EPSP amplitude does not however appear to result from NTPDase inhibition as it persists when both adenosine and ATP (P2Y and P2X) receptors are blocked. An increase in paired pulse ratio and a reduction in presynaptic volley amplitude suggest that there is a presynaptic component of POM-1 action which reduces glutamate release. POM-1 produced similar inhibition at climbing fibre synapses and at hippocampal CA1 pyramidal synapses. Thus although POM-1 is more effective than ARL 67156 at blocking ATP breakdown its usefulness is limited by off-target actions on synaptic transmission.

Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury.[Pubmed:17442731]

FASEB J. 2007 Sep;21(11):2863-73.

Previous studies showed increased extracellular nucleotides during renal ischemia-reperfusion. While nucleotides represent the main source for extracellular adenosine and adenosine signaling contributes to renal protection from ischemia, we hypothesized a role for ecto-nucleoside-triphosphate-diphosphohydrolases (E-NTPDases) in renal protection. We used a model of murine ischemia-reperfusion and in situ ischemic preconditioning (IP) via a hanging weight system for atraumatic renal artery occlusion. Initial studies with a nonspecific inhibitor of E-NTPDases (POM-1) revealed inhibition of renal protection by IP. We next pursued transcriptional responses of E-NTPDases (E-NTPDase1-3, and 8) to renal IP, and found a robust and selective induction of E-NTPDase1/CD39 transcript and protein. Moreover, based on clearance studies, plasma electrolytes, and renal tubular histology, IP protection was abolished in gene-targeted mice for cd39 whereas increased renal adenosine content with IP was attenuated. Furthermore, administration of apyrase reconstituted renal protection by IP in cd39-/- mice. Finally, apyrase treatment of wild-type mice resulted in increased renal adenosine concentrations and a similar degree of renal protection from ischemia as IP treatment. Taken together, these data identify CD39-dependent nucleotide phosphohydrolysis in renal protection. Moreover, the present studies suggest apyrase treatment as a novel pharmacological approach to renal diseases precipitated by limited oxygen availability.

Polyoxometalates--a new class of potent ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitors.[Pubmed:16997558]

Bioorg Med Chem Lett. 2006 Dec 1;16(23):5943-7.

Polyoxotungstates were identified as potent inhibitors of NTPDases1, 2, and 3. The most potent compound was K(6)H(2)[TiW(11)CoO(40)], exhibiting K(i) values of 0.140 microM (NTPDase1), 0.910 microM (NTPDase2), and 0.563 microM (NTPDase3). One of the compounds, (NH(4))(18)[NaSb(9)W(21)O(86)], was selective for NTPDases2 and 3 versus NTPDase1. NTPDase inhibition might contribute to the described biological effects of polyoxometalates, including their anti-cancer activity.

Sodium metatungstate (POM-1) is a potent ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitor, with Ki values of 2.58 μM, 3.26 μM, and 28.8 μM for NTPDase 1, NTPDase 3 and NTPDase 2 respectively. Sodium metatungstate (POM-1) inhibits ATP breakdown but also blocks central synaptic transmission, an action independent of NTPDase inhibition.

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