THIAZOLIDINE DIONES, SPECIFIC LIGANDS OF THE NUCLEAR RECEPTOR RETINOID Z RECEPTOR RETINOID ACID RECEPTOR-RELATED ORPHAN RECEPTOR-ALPHA WITHPOTENT ANTIARTHRITIC ACTIVITY

Rat adjuvant arthritis is a chronic T cell-dependent autoimmune diseas e with many similarities to rheumatoid arthritis. We have identified a class of thiazolidine diones with high potency in suppressing chronic inflammation and joint destruction in this experimental model. The le ad compound CGP 52608 (1-(3-allyl-4-oxothiazolidine-2-ylidene)-4- meth ylthiosemicarbazone) exhibits antiarthritic activity at dailyoral dose s between 0.01 and 1 mg/kg and was shown to specifically activate the retinoid Z receptor/retinoid acid receptor-related orphan receptor alp ha (RZR/ROR alpha) in low nanomolar concentrations, This receptor is a novel member of the superfamily of ligand-inducible transcription fac tors, and we have recently identified the pineal gland hormone melaton in as a natural ligand. Structure-activity relationship studies with 1 3 closely related analogues of CGP 52608 revealed a striking correlati on between RZR/ROR alpha activation and antiarthritic activity. We the refore suggest that nuclear signaling via RZR/ROR alpha is a key mecha nism in mediating the antiarthritic effects of these thiazolidine dion es and may open a novel therapeutic approach for the treatment of rheu matoid arthritis and other autoimmune diseases. The existence of a nuc lear melatonin receptor may lead to a better understanding of the immu nomodulatory actions of melatonin.