Synthesis and biological evaluation of several structural analogs of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand

Abstract 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.