|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1998 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1997 : ¥1,800,000 (Direct Cost : ¥1,800,000)
An endogenous carmabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca^<2+> concentrations in NG1O8-15 cells through a cannabinoid CB1 receptor-dependent mechanism. We examined the activities of a number of relevant compounds (2-arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2-arachidonoylglycerol is the most potent compound examined so far. We confirmed that a metabolically stable ether-linked analogue of 2-arachidonoylglycerol possesses appreciable agonistic activity, although its activity was apparently lower than that of 2-arachidonoylglycerol. These results strongly suggested that the cannabinoid CB1 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic physiological ligand for the cannabinoid CB1 receptor.
Next we examined the molecular species compositions of monoacyiglycerols obtained from various rattissues by reverse-phase HPLC and GC-MS analyses. We confirmed that 2-arachidonoylglycerol, an endogenous cannabinoid receptor agonist, is one of most abundant molecular species of monoacylglycerols in the brain. Substantial amounts of 2-arachidonoylglycerol were also found in liver, spleen, lung and kidney. We also found that human endothelial cells produce 2-arachidonoylglycerol when stimulated with thrombin. We confirmed that human vascular smooth muscle cells possesses the cannabinoid CB1 receptor mRNA.It is possible, therefore, that 2-arachidonoylglycerol, an endogenous cannabinoid receptor agonist, is a possible vasomodulator.