Abstract
The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.
Keywords:
2-Arachidonoylglycerol; Anandamide; Cyclooxygenase-2; Drug development; Fatty acid amide hydrolase; Monoacylglycerol lipase; Pain.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Amidohydrolases / antagonists & inhibitors
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Amidohydrolases / metabolism
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Analgesics / pharmacology*
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Cyclooxygenase 2 Inhibitors / pharmacology
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Drug Discovery*
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Endocannabinoids / antagonists & inhibitors*
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Endocannabinoids / metabolism
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Enzyme Inhibitors / pharmacology*
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Fatty Acid-Binding Proteins / antagonists & inhibitors
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Fatty Acid-Binding Proteins / metabolism
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Humans
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Hydrolysis
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Molecular Targeted Therapy
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Monoacylglycerol Lipases / antagonists & inhibitors
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Monoacylglycerol Lipases / metabolism
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Signal Transduction / drug effects*
Substances
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Analgesics
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Anti-Inflammatory Agents
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Cyclooxygenase 2 Inhibitors
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Endocannabinoids
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Enzyme Inhibitors
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FABP5 protein, human
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Fatty Acid-Binding Proteins
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Monoacylglycerol Lipases
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Amidohydrolases
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NAAA protein, human
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fatty-acid amide hydrolase