SSR125329A, a high affinity σ receptor ligand with potent anti-inflammatory properties

• Published in: European journal of pharmacology Vol. 456; no. 1; pp. 123 - 131
• Main Authors: Bourrié, Bernard, Bribes, Estelle, De Nys, Nathalie, Esclangon, Martine, Garcia, Laurent, Galiègue, Sylvaine, Lair, Pierre, Paul, Raymond, Thomas, Corinne, Vernières, Jean-Claude, Casellas, Pierre
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 05.12.2002; Elsevier
• Subjects: Adamantane - analogs & derivatives; Adamantane - pharmacology; Animals; Anti-Inflammatory Agents - pharmacology; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - prevention & control; Autoimmune disease; Binding, Competitive; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Division - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Enterotoxins - pharmacology; Female; Graft vs Host Disease - prevention & control; Immunomodulators; Interleukin-10; Interleukin-10 - metabolism; Ligands; Lipopolysaccharides - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred Strains; Pharmacology. Drug treatments; Protein Subunits - metabolism; Receptors, sigma - drug effects; Receptors, sigma - metabolism; Spleen - cytology; Spleen - drug effects; Steroid Isomerases - metabolism; Syndrome; TNF-α (tumor necrosis factor); Tumor Necrosis Factor-alpha - metabolism; σ Receptor; Autoimmune disease; σ Receptor; TNF-α (tumor necrosis factor); Interleukin-10; Cell proliferation; Agonist; Rat; Diseases of the osteoarticular system; Sigma receptor; Inflammatory joint disease; Splenocyte; Immunotherapy; Antirheumatic agent; Mechanism of action; Tumor necrosis factor α; Spleen; Immunopathology; Treatment efficiency; Rodentia; Antiinflammatory agent; Graft versus host reaction; In vitro; Immunomodulator; In vivo; Vertebrata; Chronic; Mammalia; Treatment; Mouse; Animal; Rheumatoid arthritis; Interleukin 10
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(02)02646-8

SSR125329A ([( Z)-3-(4-Adamantan-2-yl-3,5-dichloro-phenyl)-allyl]-cyclohexyl-ethyl-amine) is a new ligand exhibiting high affinity for σ 1 and σ 2 receptors and for the human Δ8–Δ7-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-α) 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 σ receptor ligands may represent a new effective approach for rheumatoid arthritis treatment.