Inhibition of anandamide hydrolysis in rat brain tissue by (E)-6-(bromomethylene) tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one

Anandamide, an endogenous cannabinoid substance, is hydrolyzed by an amidohydrolase activity present in rat brain and liver. We report that the bromoenol lactone, (E)-6-(bromomethylene) tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BTNP), is a potent inhibitor of this enzyme activity. BTNP prevented...

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Bibliographic Details
Published in:FEBS letters 1997-02, Vol.403 (3), p.263-267
Main Authors: Beltramo, Massimiliano, di Tomaso, Emmanuelle, Piomelli, Daniele
Format: Article
Language:English
Subjects:
Amidohydrolase
Amidohydrolases - antagonists & inhibitors
Anandamide
Animal biology
Animals
Arachidonic Acids - metabolism
Astrocytes - enzymology
Brain - enzymology
Bromoenol lactone
Cannabinoid
Cellular Biology
Cerebral Cortex - cytology
Cerebral Cortex - enzymology
Endocannabinoids
Enzyme Inhibitors - pharmacology
Hydrolysis - drug effects
Ionophores - pharmacology
Life Sciences
Microsomes, Liver - enzymology
Naphthalenes - pharmacology
Neurons - enzymology
Pharmaceutical sciences
Pharmacology
Phosphatidylcholines - metabolism
Phosphatidylethanolamines - metabolism
Phospholipase A 2
Phospholipase A2
Polyunsaturated Alkamides
Pyrones - pharmacology
Rats
Rats, Wistar
Reproductive Biology
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Summary:Anandamide, an endogenous cannabinoid substance, is hydrolyzed by an amidohydrolase activity present in rat brain and liver. We report that the bromoenol lactone, (E)-6-(bromomethylene) tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BTNP), is a potent inhibitor of this enzyme activity. BTNP prevented anandamide hydrolysis in rat brain microsomes with an IC 50 of 0.8±0.3 μM. Kinetic and dialysis experiments indicated that this effect was non-competitive and irreversible. After chromatographic fractionation of the enzyme activity, BTNP was still effective, suggesting that it interacts directly with the enzyme. Anandamide hydrolysis was 12-fold greater in rat cortical neurons (1.94±0.1 pmol/min/mg protein) than in cortical astrocytes (0.16±0.01 pmol/min/mg protein) and, in either cell type, it was inhibited by BTNP (IC 50=0.1 μM in neurons). These results suggest that BTNP may provide a useful lead for the development of novel inhibitors of anandamide hydrolysis. © Federation of European Biochemical Societies.
ISSN:0014-5793
1873-3468
DOI:10.1016/S0014-5793(97)00061-6