URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain

Susanna M Saario; Ville Palomäki; Marko Lehtonen; Tapio Nevalainen; Tomi Järvinen; Jarmo T Laitinen

doi:10.1016/j.chembiol.2006.07.008

URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain

Chem Biol. 2006 Aug;13(8):811-4. doi: 10.1016/j.chembiol.2006.07.008.

Authors

Susanna M Saario¹, Ville Palomäki, Marko Lehtonen, Tapio Nevalainen, Tomi Järvinen, Jarmo T Laitinen

Affiliation

¹ Department of Pharmaceutical Chemistry, Department of Physiology, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. susanna.saario@uku.fi

PMID: 16931330
DOI: 10.1016/j.chembiol.2006.07.008

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

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / chemistry
Aniline Compounds / pharmacology*
Animals
Arachidonic Acids / antagonists & inhibitors
Arachidonic Acids / pharmacology
Arachidonic Acids / physiology*
Benzoxazines / chemistry
Benzoxazines / pharmacology*
Biphenyl Compounds / pharmacology
Brain / drug effects*
Brain / metabolism*
Catalysis
Endocannabinoids
GTP-Binding Proteins / drug effects
GTP-Binding Proteins / metabolism
Glycerides / antagonists & inhibitors
Glycerides / pharmacology
Glycerides / physiology*
Hydrolysis / drug effects
Lectins
Lectins, C-Type / chemistry
Male
Membrane Proteins / chemistry
Membrane Proteins / pharmacology
Molecular Structure
Rats
Rats, Wistar
Receptors, Cell Surface
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

Aniline Compounds
Arachidonic Acids
Benzoxazines
Biphenyl Compounds
Clec10a protein, rat
Endocannabinoids
Glycerides
Lectins
Lectins, C-Type
Membrane Proteins
Receptors, Cell Surface
URB 754
URB602
glyceryl 2-arachidonate
GTP-Binding Proteins