URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain.
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.
Saario
Susanna M
SM
Department of Pharmaceutical Chemistry, Department of Physiology, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. susanna.saario@uku.fi
Palomäki
Ville
V
Lehtonen
Marko
M
Nevalainen
Tapio
T
Järvinen
Tomi
T
Laitinen
Jarmo T
JT
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002384:Catalysis; D063388:Endocannabinoids; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D006868:Hydrolysis / Q000187:drug effects; D037102:Lectins; D037181:Lectins, C-Type / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D001095:Arachidonic Acids; D048588:Benzoxazines; D001713:Biphenyl Compounds; C023339:Clec10a protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D037102:Lectins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C514879:URB 754; C501835:URB602; C094503:glyceryl 2-arachidonate; D019204:GTP-Binding Proteins