Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2
| Autor: | Ruth A. Ross, Carolyn Tanner, Roger G. Pertwee, Douglas McHugh, Raphael Mechoulam |
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| Rok vydání: | 2007 |
| Předmět: |
Agonist
Cannabinoid receptor medicine.drug_class Neutrophils medicine.medical_treatment 2-Arachidonoylglycerol Biology Pharmacology Receptor Cannabinoid CB2 chemistry.chemical_compound Receptor Cannabinoid CB1 Cannabinoid Receptor Modulators medicine Humans Binding Sites Dose-Response Relationship Drug Cannabinoids Endocannabinoid system Microglial cell migration Chemotaxis Leukocyte Virodhamine chemistry GPR55 Molecular Medicine lipids (amino acids peptides and proteins) Cannabinoid |
| Zdroj: | Molecular pharmacology. 73(2) |
| ISSN: | 1521-0111 |
| Popis: | Here, we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids, and related compounds. The endocannabinoids virodhamine and N-arachidonoyl dopamine are potent inhibitors of N-formyl-l-methionyl-l-leucyl-l-phenylalanine-induced migration of human neutrophils, with IC(50) values of 0.2 and 8.80 nM, respectively. The endocannabinoid anandamide inhibits human neutrophil migration at nanomolar concentrations in a biphasic manner. The phytocannabinoid (-)-cannabidiol is a partial agonist, being approximately 40 fold more potent than (+)-cannabidiol; abnormal-cannabidiol is a full agonist. Furthermore, the abnormal-cannabidiol (CBD) analog trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-methyl-1,3-benzenediol (O-1602) inhibits migration, with an IC(50) value of 33 nM. This reported profile of agonist efficacy and potency parallels with the pharmacology of the novel "abnormal-cannabidiol" receptor or a related orphan G protein-coupled receptor, which are already known to modulate cell migration. Although having no effect alone, N-arachidonoyl l-serine attenuated inhibition of human neutrophil migration induced by anandamide, virodhamine, and abnormal-CBD. Our data also suggest that there is cross-talk/negative co-operativity between the cannabinoid CB(2) receptor and this novel target: CB(2) receptor antagonists significantly enhance the inhibition observed with anandamide and virodhamine. This study reveals that certain endogenous lipids, phytocannabinoids, and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB(1) and CB(2) receptors; this target is antagonized by the endogenous compound N-arachidonoyl l-serine. Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions. |
| Databáze: | OpenAIRE |
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