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.