Abstract
Previous studies indicate that in brain tissue the endocannabinoid 2-AG is inactivated by monoglyceride lipase (MGL)-catalyzed hydrolysis, and a recent report has indicated that MGL activity could be specifically inhibited by URB754 . In the present study, URB754 failed to inhibit 2-AG hydrolysis in rat brain preparations. In addition, brain cryosections were employed to assess whether URB754 could facilitate the detection of 2-AG-stimulated G protein activity. Nevertheless, whereas pretreatment with PMSF readily allowed detection of 2-AG-stimulated G protein activity, URB754 was ineffective. In contrast to previous claims, brain FAAH activity was also resistant to URB754. Thus, in our hands URB754 was not able to block the endocannabinoid-hydrolyzing enzymes and cannot serve as a lead structure for future development of MGL-specific inhibitors.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology*
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Animals
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Arachidonic Acids / antagonists & inhibitors
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Arachidonic Acids / pharmacology
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Arachidonic Acids / physiology*
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Benzoxazines / chemistry
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Benzoxazines / pharmacology*
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Biphenyl Compounds / pharmacology
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Brain / drug effects*
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Brain / metabolism*
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Catalysis
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Endocannabinoids
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GTP-Binding Proteins / drug effects
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GTP-Binding Proteins / metabolism
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Glycerides / antagonists & inhibitors
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Glycerides / pharmacology
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Glycerides / physiology*
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Hydrolysis / drug effects
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Lectins
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Lectins, C-Type / chemistry
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Male
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Membrane Proteins / chemistry
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Membrane Proteins / pharmacology
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Molecular Structure
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Rats
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Rats, Wistar
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Receptors, Cell Surface
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Signal Transduction / drug effects
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Structure-Activity Relationship
Substances
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Aniline Compounds
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Arachidonic Acids
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Benzoxazines
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Biphenyl Compounds
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Clec10a protein, rat
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Endocannabinoids
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Glycerides
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Lectins
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Lectins, C-Type
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Membrane Proteins
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Receptors, Cell Surface
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URB 754
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URB602
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glyceryl 2-arachidonate
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GTP-Binding Proteins