Beta-caryophyllene is a dietary cannabinoid.
The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zurich, 8092 Zürich, Switzerland. juerg.gertsch@pharma.ethz.ch
Jürg
J
Gertsch
Marco
M
Leonti
Stefan
S
Raduner
Ildiko
I
Racz
Jian-Zhong
JZ
Chen
Xiang-Qun
XQ
Xie
Karl-Heinz
KH
Altmann
Meliha
M
Karsak
Andreas
A
Zimmer
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002186:Cannabinoids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002188:Cannabis / Q000737:chemistry; D002351:Carrageenan; D002478:Cells, Cultured; D019295:Computational Biology; D004032:Diet; D004487:Edema / Q000139:chemically induced / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000201:enzymology; D009822:Oils, Volatile / Q000737:chemistry; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D002186:Cannabinoids; D053583:Interleukin-1beta; D008024:Ligands; D008070:Lipopolysaccharides; D009822:Oils, Volatile; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; C024714:caryophyllene; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go