Thiazolidine diones, specific ligands of the nuclear receptor retinoid Z receptor/retinoid acid receptor-related orphan receptor alpha with potent antiarthritic activity.
Rat adjuvant arthritis is a chronic T cell-dependent autoimmune disease 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 lead compound CGP 52608 (1-(3-allyl-4-oxothiazolidine-2-ylidene)-4-methylthiosemicarbazone) exhibits antiarthritic activity at daily oral doses between 0.01 and 1 mg/kg and was shown to specifically activate the retinoid Z receptor/retinoid acid receptor-related orphan receptor alpha (RZR/RORalpha) in low nanomolar concentrations. This receptor is a novel member of the superfamily of ligand-inducible transcription factors, and we have recently identified the pineal gland hormone melatonin as a natural ligand. Structure-activity relationship studies with 13 closely related analogues of CGP 52608 revealed a striking correlation between RZR/RORalpha activation and antiarthritic activity. We therefore suggest that nuclear signaling via RZR/RORalpha is a key mechanism in mediating the antiarthritic effects of these thiazolidine diones and may open a novel therapeutic approach for the treatment of rheumatoid arthritis and other autoimmune diseases. The existence of a nuclear melatonin receptor may lead to a better understanding of the immunomodulatory actions of melatonin.
Missbach
M
M
Pharma-Forschung, Ciba-Geigy AG, CH-4002 Basel, Switzerland.
Jagher
B
B
Sigg
I
I
Nayeri
S
S
Carlberg
C
C
Wiesenberg
I
I
D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008297:Male; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D051381:Rats; D011917:Rats, Inbred Lew; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D044094:Receptors, Melatonin; D018168:Receptors, Retinoic Acid; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D009281:Naphthalenes
D000081:Acetamides; D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D008550:Melatonin; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D018168:Receptors, Retinoic Acid; D013844:Thiazoles; D013882:Thiosemicarbazones; D015534:Trans-Activators; C000598704:Roralpha protein, rat; C084711:agomelatine; D009281:Naphthalenes; C092451:CGP 52608