Alpha-methylated derivatives of 2-arachidonoyl glycerol: synthesis, CB1 receptor activity, and enzymatic stability.
Alpha-methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPgammaS binding assay, and the enzymatic stability of alpha-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the alpha-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.
Parkkari
Teija
T
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. Teija.Parkkari@uku.fi
Myllymäki
Mikko
M
Savinainen
Juha R
JR
Saario
Susanna M
SM
Castillo-Meléndez
Joel A
JA
Laitinen
Jarmo T
JT
Nevalainen
Tapio
T
Koskinen
Ari M P
AM
Järvinen
Tomi
T
D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D063388:Endocannabinoids; D004795:Enzyme Stability / Q000187:drug effects; D005989:Glycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008745:Methylation; D015394:Molecular Structure; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate