Selective Cannabinoid 2 Receptor Agonists as Potential Therapeutic Drugs for the Treatment of Endotoxin-Induced Uveitis

被引:23
作者
Porter, Richard Frederick [1 ]
Szczesniak, Anna-Maria [1 ]
Toguri, James Thomas [1 ]
Gebremeskel, Simon [2 ]
Johnston, Brent [2 ,3 ]
Lehmann, Christian [1 ,2 ,4 ]
Fingerle, Juergen [5 ]
Rothenhaeusler, Benno [5 ]
Perret, Camille [5 ]
Rogers-Evans, Mark [5 ]
Kimbara, Atsushi [5 ]
Nettekoven, Matthias [5 ]
Guba, Wolfgang [5 ]
Grether, Uwe [5 ]
Ullmer, Christoph [5 ]
Kelly, Melanie E. M. [1 ,4 ,6 ]
机构
[1] Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4R2, Canada
[2] Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS B3H 4R2, Canada
[3] Dalhousie Univ, Dept Pediat, Halifax, NS B3H 4R2, Canada
[4] Dalhousie Univ, Dept Anesthesia Pain Management & Perioperat Care, Halifax, NS B3H 4R2, Canada
[5] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, CH-4070 Basel, Switzerland
[6] Dalhousie Univ, Dept Ophthalmol & Visual Sci, Halifax, NS B3H 2Y9, Canada
关键词
cannabinoid; 2; receptor; synthetic cannabinoids; selective cannabinoid ligands; structure-activity relationship; uveitis; anti-inflammatory; CENTRAL-NERVOUS-SYSTEM; ENDOCANNABINOID SYSTEM; CB2; RECEPTOR; MONOCLONAL-ANTIBODY; MICROGLIAL CELLS; PROTECTS; ACTIVATION; PREVENTION; FIBROSIS; TARGET;
D O I
10.3390/molecules24183338
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
(1) Background: The cannabinoid 2 receptor (CB2R) is a promising anti-inflammatory drug target and development of selective CB2R ligands may be useful for treating sight-threatening ocular inflammation. (2) Methods: This study examined the pharmacology of three novel chemically-diverse selective CB2R ligands: CB2R agonists, RO6871304, and RO6871085, as well as a CB2R inverse agonist, RO6851228. In silico molecular modelling and in vitro cell-based receptor assays were used to verify CB2R interactions, binding, cell signaling (ss-arrestin and cAMP) and early absorption, distribution, metabolism, excretion, and toxicology (ADMET) profiling of these receptor ligands. All ligands were evaluated for their efficacy to modulate leukocyte-neutrophil activity, in comparison to the reported CB2R ligand, HU910, using an in vivo mouse model of endotoxin-induced uveitis (EIU) in wild-type (WT) and CB2R-/- mice. The actions of RO6871304 on neutrophil migration and adhesion were examined in vitro using isolated neutrophils from WT and CB2R-/- mice, and in vivo in WT mice with EIU using adoptive transfer of WT and CB2R-/- neutrophils, respectively. (3) Results: Molecular docking studies indicated that RO6871304 and RO6871085 bind to the orthosteric site of CB2R. Binding studies and cell signaling assays for RO6871304 and RO6871085 confirmed high-affinity binding to CB2R and selectivity for CB2R > CB1R, with both ligands acting as full agonists in cAMP and ss-arrestin assays (EC(50)s in low nM range). When tested in EIU, topical application of RO6871304 and RO6871085 decreased leukocyte-endothelial adhesion and this effect was antagonized by the inverse agonist, RO6851228. The CB2R agonist, RO6871304, decreased in vitro neutrophil migration of WT neutrophils but not neutrophils from CB2R-/-, and attenuated adhesion of adoptively-transferred leukocytes in EIU. (4) Conclusions: These unique ligands are potent and selective for CB2R and have good immunomodulating actions in the eye. RO6871304 and RO6871085, as well as HU910, decreased leukocyte adhesion in EIU through inhibition of resident ocular immune cells. The data generated with these three structurally-diverse and highly-selective CB2R agonists support selective targeting of CB2R for treating ocular inflammatory diseases.
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页数:20
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