Synthesis and biological evaluation of several structural analogs of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand.
2-Arachidonoylglycerol (2-AG (1)) is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). There is growing evidence that 2-arachidonoylglycerol plays important physiological and pathophysiological roles in various mammalian tissues and cells, though the details remain to be clarified. In this study, we synthesized several remarkable analogs of 2-arachidonoylglycerol, closely related in chemical structure to 2-arachidonoylglycerol: an analog containing an isomer of arachidonic acid with migrated olefins (2-AGA118 (3)), an analog containing a one-carbon shortened fatty acyl moiety (2-AGA113 (4)), an analog containing an one-carbon elongated fatty acyl moiety (2-AGA114 (5)), a hydroxy group-containing analog (2-AGA105 (6)), a ketone group-containing analog (2-AGA109 (7)), and a methylene-linked analog (2-AGA104 (8)). We evaluated their biological activities as cannabinoid receptor agonists using NG108-15 cells which express the CB1 receptor and HL-60 cells which express the CB2 receptor. Notably, these structural analogs of 2-arachidonoylglycerol exhibited only weak agonistic activities toward either the CB1 receptor or the CB2 receptor, which is in good contrast to 2-arachidonoylglycerol which acted as a full agonist at these cannabinoid receptors. These results clearly indicate that the structure of 2-arachidonoylglycerol is strictly recognized by the cannabinoid receptors (CB1 and CB2) and provide further evidence that the cannabinoid receptors are primarily the intrinsic receptors for 2-arachidonoylglycerol.
Suhara
Yoshitomo
Y
Department of Pharmaceutical Chemistry, Faculty of Pharmcaceutical Sciences, Teikyo University, Sagamihara, Kanagawa 199-0195, Japan.
Oka
Saori
S
Kittaka
Atsushi
A
Takayama
Hiroaki
H
Waku
Keizo
K
Sugiura
Takayuki
T
D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists; D002460:Cell Line; D063388:Endocannabinoids; D005989:Glycerides / Q000138:chemical synthesis* / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; D007202:Indicators and Reagents; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; C094503:glyceryl 2-arachidonate