SSR125329A, a high affinity sigma receptor ligand with potent anti-inflammatory properties.
SSR125329A ([(Z)-3-(4-Adamantan-2-yl-3,5-dichloro-phenyl)-allyl]-cyclohexyl-ethyl-amine) is a new ligand exhibiting high affinity for sigma(1) and sigma(2) receptors and for the human Delta8-Delta7-sterol isomerase. Here we show that this molecule has potent immunoregulatory properties both in vitro and in vivo. SSR125329A inhibited staphylococcal enterotoxin B-induced mouse splenocyte proliferation in vitro, whereas in vivo it enhanced lipopolysaccharide-induced systemic release of interleukin-10 while simultaneously inhibiting tumor necrosis factor-alpha (TNF-alpha) synthesis. It also prevented graft-versus-host disease in B6D2F1 mice and protected Mrl/lpr mice against the development of its spontaneous rheumatoid-like syndrome. There is high interplay of pro- and anti-inflammatory cytokines in inflammatory processes, particularly in human rheumatoid arthritis. The results of this study provide substantial evidence that sigma receptor ligands may represent a new effective approach for rheumatoid arthritis treatment.
Bourrié
Bernard
B
Sanofi-Synthelabo Recherche, Department of Immunology-Oncology, 371 rue du Professeur Blayac, 34184 Montpellier, France. bernard.bourrie@sanofi-synthelabo.com
Bribes
Estelle
E
De Nys
Nathalie
N
Esclangon
Martine
M
Garcia
Laurent
L
Galiègue
Sylvaine
S
Lair
Pierre
P
Paul
Raymond
R
Thomas
Corinne
C
Vernières
Jean-Claude
JC
Casellas
Pierre
P
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000517:prevention & control; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D016753:Interleukin-10 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D021122:Protein Subunits / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013251:Steroid Isomerases / Q000378:metabolism; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004768:Enterotoxins; D008024:Ligands; D008070:Lipopolysaccharides; D021122:Protein Subunits; D017480:Receptors, sigma; C473962:SSR125329A; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal; D013251:Steroid Isomerases; D000218:Adamantane