Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetamides / metabolism
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Acetamides / pharmacology
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Adjuvants, Immunologic / metabolism
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / metabolism
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Arthritis, Experimental / drug therapy
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Arthritis, Experimental / immunology
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Arthritis, Experimental / metabolism
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Autoimmune Diseases / drug therapy
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Autoimmune Diseases / immunology
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Autoimmune Diseases / metabolism
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Ligands
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Male
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Melatonin / metabolism
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Melatonin / pharmacology
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Nuclear Receptor Subfamily 1, Group F, Member 1
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Rats
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Rats, Inbred Lew
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Receptors, Cell Surface / drug effects
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Receptors, Cell Surface / metabolism*
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Receptors, Cytoplasmic and Nuclear / drug effects
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Melatonin
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Receptors, Retinoic Acid*
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Structure-Activity Relationship
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Thiazoles / chemistry
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Thiazoles / metabolism*
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Thiazoles / pharmacology*
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Thiosemicarbazones / chemistry
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Thiosemicarbazones / metabolism
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Thiosemicarbazones / pharmacology
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Trans-Activators / drug effects
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Trans-Activators / metabolism*
Substances
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Acetamides
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Adjuvants, Immunologic
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Anti-Inflammatory Agents, Non-Steroidal
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Ligands
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Nuclear Receptor Subfamily 1, Group F, Member 1
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Receptors, Cell Surface
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Receptors, Cytoplasmic and Nuclear
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Receptors, Melatonin
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Receptors, Retinoic Acid
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Roralpha protein, rat
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Thiazoles
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Thiosemicarbazones
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Trans-Activators
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agomelatine
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CGP 52608
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Melatonin