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

Research output: Contribution to journalArticle

250 Citations (Scopus)

Abstract

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
Volume274
Issue number5
DOIs
Publication statusPublished - 1999 Jan 29
Externally publishedYes

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Cannabinoid Receptor CB1
Ether
Cannabinoid Receptor Agonists
Neurotransmitter Agents
2-arachidonylglycerol
Cannabinoids
Arachidonic Acid
Assays
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor : Structure-activity relationship of 2-arachidonoylglycerol, ether- linked analogues, and related compounds. / Sugiura, Takayuki; Kodaka, Tomoko; Nakane, Shinji; Miyashita, Tomoyuki; Kondo, Sachiko; Suhara, Yoshitomo; Takayama, Hiroaki; Waku, Keizo; Seki, Chiyo; Baba, Naomichi; Ishima, Yoshio.

In: Journal of Biological Chemistry, Vol. 274, No. 5, 29.01.1999, p. 2794-2801.

Research output: Contribution to journalArticle

Sugiura, Takayuki ; Kodaka, Tomoko ; Nakane, Shinji ; Miyashita, Tomoyuki ; Kondo, Sachiko ; Suhara, Yoshitomo ; Takayama, Hiroaki ; Waku, Keizo ; Seki, Chiyo ; Baba, Naomichi ; Ishima, Yoshio. / Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor : Structure-activity relationship of 2-arachidonoylglycerol, ether- linked analogues, and related compounds. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 5. pp. 2794-2801.
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AU - Kodaka, Tomoko

AU - Nakane, Shinji

AU - Miyashita, Tomoyuki

AU - Kondo, Sachiko

AU - Suhara, Yoshitomo

AU - Takayama, Hiroaki

AU - Waku, Keizo

AU - Seki, Chiyo

AU - Baba, Naomichi

AU - Ishima, Yoshio

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