The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors

J Pharmacol Exp Ther. 2005 Aug;314(2):868-75. doi: 10.1124/jpet.105.085282. Epub 2005 May 18.


Noladin ether (NE) is a putative endogenously occurring cannabinoid demonstrating agonist activity at CB1 receptors. Because of reported selective affinity for CB1 receptors, the pharmacological actions of NE at CB2 receptors have not been examined. Therefore, the purpose of this study was to characterize the binding and functional properties of NE at human CB2 receptors stably expressed in Chinese hamster ovary (CHO) cells as well as in HL-60 cells, which express CB2 receptors endogenously. Surprisingly, in transfected CHO cells, NE exhibits a relatively high nanomolar affinity for CB2 receptors (K(i) = 480 nM), comparable to that observed for the endocannabinoid 2-arachidonoyl glycerol (2-AG) (K(i) = 1016 nM). Furthermore, NE activates G proteins and inhibits the intracellular effector adenylyl cyclase with equivalent efficacy relative to the full cannabinoid agonists 2-AG and CP 55,940 (CP) [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol]. The rank order of potency for G protein activation and effector regulation by the three agonists is similar to their apparent affinity for CB2 receptors; CP > NE > or = 2-AG. Regulation of adenylyl cyclase activity by all agonists is inhibited by pertussis toxin pretreatment or by coincubation with AM630 [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone], a CB2 antagonist. Chronic treatment with NE or CP results in CB2 receptor desensitization and down-regulation. All agonists also inhibit adenylyl cyclase activity in HL-60 cells. Together, these data indicate that NE acts as a full agonist at human CB2 receptors and thus might have important physiological functions at peripheral cannabinoid receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases / metabolism
  • Analgesics / pharmacology
  • Animals
  • Arachidonic Acids / pharmacology
  • Binding, Competitive / drug effects
  • Biotransformation / drug effects
  • CHO Cells
  • Cricetinae
  • Cyclic AMP / metabolism
  • Cyclohexanols / pharmacology
  • Down-Regulation / drug effects
  • Endocannabinoids
  • Enzyme Inhibitors
  • GTP-Binding Proteins / metabolism
  • Glycerides / pharmacology*
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • HL-60 Cells
  • Humans
  • In Vitro Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptors, G-Protein-Coupled / drug effects
  • Transfection


  • Adenylyl Cyclase Inhibitors
  • Analgesics
  • Arachidonic Acids
  • Cyclohexanols
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Receptors, G-Protein-Coupled
  • noladin ether
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • glyceryl 2-arachidonate
  • Cyclic AMP
  • GTP-Binding Proteins
  • Adenylyl Cyclases