Synthesis and biological activities of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues.
We synthesized 2-arachidonoylglycerol (1), an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues. Compound 1 was synthesized from 1,3-benzylideneglycerol (6) and arachidonic acid in the presence of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine followed by treatment with boric acid and trimethyl borate. An ether-linked analogue of 2-arachidonoylglycerol (2) was synthesized from 6 and 5,8,11,14-eicosatetraenyl iodide (9). The ether-linked analogues of 2-palmitoylglycerol (4) and 2-oleoyglycerol (5) were synthesized from 6 and hexadecyl iodide (12) and 9-octadecenyl iodide (14), respectively. We confirmed that 1 stimulates NG108-15 cells to induce rapid transient elevation of the intracellular free Ca2+ concentrations through a CB1 receptor-dependent mechanism. Noticeably, 2 exhibited appreciable agonistic activity, although its activity was significantly lower than that of 1. Compound 2 would be a useful tool in exploring the physiological significance of 1, because this compound is resistant to hydrolyzing enzymes in contrast to 1. On the other hand, the ether-linked analogues of either 4 or 5 failed to act as a CB1 receptor agonist. Compounds 4 and 5 would also be valuable as control molecules in experiments where 2 is employed.
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan.
Y
Y
Suhara
H
H
Takayama
S
S
Nakane
T
T
Miyashita
K
K
Waku
T
T
Sugiura
D000818:Animals; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018377:Neurotransmitter Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D018377:Neurotransmitter Agents; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C094503:glyceryl 2-arachidonate