A new phospholipase A2 inhibitor, unrelated to substrate analogues: kinetic characterization of the inhibition of secretory phospholipases A2 by PMS 832

Starting from a series of compounds which were known to be PAF antagonists, we have synthesized molecules that are good inhibitors of PLA2s of groups I or II, with IC50 in the micromolar range (Binisti et al., 1997). In this report we investigate the mechanism of inhibition of bovine and porcine pan...

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Bibliographic Details
Published in:Journal of lipid mediators and cell signalling 1997-07, Vol.16 (3), p.171-187
Main Authors: Binisti, C, Mounier, C, Touboul, E, Heymans, F, Bon, C, Godfroid, J J
Format: Article
Language:English
Subjects:
Animals
Bacillus - enzymology
Blood Platelets - enzymology
Cattle
Chromatography, Thin Layer
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Fluorescent Dyes - metabolism
Kinetics
Male
Molecular Structure
Pancreas - enzymology
Phosphatidic Acids - metabolism
Phosphatidylcholines - metabolism
Phospholipases - metabolism
Phospholipases A - antagonists & inhibitors
Phospholipases A - secretion
Phospholipases A2
Piperazines - chemistry
Piperazines - pharmacology
Platelet Activating Factor - metabolism
Platelet Aggregation - drug effects
Rabbits
Serum Albumin, Bovine - pharmacology
Swine
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Summary:Starting from a series of compounds which were known to be PAF antagonists, we have synthesized molecules that are good inhibitors of PLA2s of groups I or II, with IC50 in the micromolar range (Binisti et al., 1997). In this report we investigate the mechanism of inhibition of bovine and porcine pancreatic phospholipases A2 (group I), and platelet lysate phospholipase A2 (group II) by one of these compounds, 1-(4'-methoxybenzoyl)-2-n-tridecylpiperazine (PMS 832). We show that PMS 832 behaves as a reversible, competitive inhibitor, with Ki values of 4.1 +/- 1.2 and 1.5 +/- 0.4 microM for porcine pancreatic phospholipase A2 and platelet lysate phospholipase A2, respectively. PMS 832 failed to inhibit platelet activation induced by several agonists and was also found to be inactive towards phospholipase C from Bacillus cereus, indicating a high specificity for phospholipase A2 inactivation. Thus, PMS 832 and its derivatives could serve as interesting tools to investigate the role of extracellular phospholipases A2 in inflammatory processes, and may be useful in the development of new anti-inflammatory agents.
ISSN:0929-7855
DOI:10.1016/S0929-7855(97)00008-4