Synthesis and biological activities of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues

Chem Pharm Bull (Tokyo). 2000 Jul;48(7):903-7. doi: 10.1248/cpb.48.903.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids*
  • Endocannabinoids
  • Glycerides / chemical synthesis*
  • Glycerides / chemistry
  • Glycerides / pharmacology
  • Mice
  • Neurotransmitter Agents / chemical synthesis*
  • Neurotransmitter Agents / chemistry
  • Neurotransmitter Agents / pharmacology
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists
  • Receptors, Drug / metabolism*
  • Tumor Cells, Cultured

Substances

  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • Neurotransmitter Agents
  • Receptors, Cannabinoid
  • Receptors, Drug
  • glyceryl 2-arachidonate