1. URB754 Has No Effect on the Hydrolysis or Signaling Capacity of 2-AG in the Rat Brain
- Author
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Ville A. B. Palomäki, Tomi Järvinen, Tapio Nevalainen, Marko Lehtonen, Jarmo T. Laitinen, and Susanna M. Saario
- Subjects
Male ,G protein ,Clinical Biochemistry ,Receptors, Cell Surface ,Arachidonic Acids ,Biology ,Biochemistry ,Catalysis ,Glycerides ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,GTP-Binding Proteins ,Lectins ,Drug Discovery ,Animals ,Structure–activity relationship ,Lectins, C-Type ,Rats, Wistar ,Receptor ,Molecular Biology ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Aniline Compounds ,Molecular Structure ,Hydrolysis ,Biphenyl Compounds ,Brain ,Membrane Proteins ,General Medicine ,Endocannabinoid system ,URB754 ,Benzoxazines ,Rats ,Monoacylglycerol lipase ,Enzyme ,chemistry ,Molecular Medicine ,PMSF ,030217 neurology & neurosurgery ,Endocannabinoids ,Signal Transduction - Abstract
SummaryPrevious 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 [1]. 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.
- Published
- 2006
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