N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties.
The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.
Milman
Garry
G
Department of Medicinal Chemistry and Natural Products, Medical Faculty, and Laboratory of Environmental Physiology, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
Maor
Yehoshua
Y
Abu-Lafi
Saleh
S
Horowitz
Michal
M
Gallily
Ruth
R
Batkai
Sandor
S
Mo
Fong-Ming
FM
Offertaler
Laszlo
L
Pacher
Pal
P
Kunos
George
G
Mechoulam
Raphael
R
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001095:Arachidonic Acids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism; D014665:Vasodilator Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; C509235:N-arachidonoyl L-serine; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014665:Vasodilator Agents; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3