Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor: Structure-activity relationship of 2-arachidonoylglycerol, ether- linked analogues, and related compounds

Takayuki Sugiura, Tomoko Kodaka, Shinji Nakane, Tomoyuki Miyashita, Sachiko Kondo, Yoshitomo Suhara, Hiroaki Takayama, Keizo Waku, Chiyo Seki, Naomichi Baba, Yoshio Ishima

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An endogenous cannabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca2+ concentrations in NG108-15 cells through a cannabinoid CB1 receptor-dependent mechanism. We examined the activities of 24 relevant compounds (2-arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2- arachidonoylglycerol is the most potent comPoUnd examined so far: its activity was detectable from as low as 0.3 nM, and the maximal response induced by 2-arachidonoylglycerol exceeded the responses induced by others. Activities of HU-210 and CP55940, potent cannabinoid receptor agonists, were also detectable from as low as 0.3 nM, whereas the maximal responses induced by these compounds were low compared with 2-arachidonoylglycerol. Anandamide was also found to act as a partial agonist in this assay system. We confirmed that free arachidonic acid failed to elicit a response. Furthermore, we found 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. We also confirmed that pretreating cells with various cannabinoid receptor agonists nullified the response induced by 2-arachidonoylglycerol, whereas pretreating cells with other neurotransmitters or neuromodulators did not affect the response. 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.

Original languageEnglish
Pages (from-to)2794-2801
Number of pages8
JournalJournal of Biological Chemistry
Issue number5
Publication statusPublished - 1999 Jan 29


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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