SPECIFIC ACTIVATION OF THE NUCLEAR RECEPTORS PPAR-GAMMA AND RORA BY THE ANTIDIABETIC THIAZOLIDINEDIONE BRL-49653 AND THE ANTIARTHRITIC THIAZOLIDINEDIONE DERIVATIVE CGP-52608

The thiazolidinedione BRL 49653 and the thiazolidinedione derivative C GP 52608 are lead compounds of two pharmacologically different classes of compounds. BRL 49653 is a high affinity ligand of peroxisome proli ferator-activated receptor gamma (PPAR gamma) and a prototype of novel antidiabetic agents, whereas CGP 52608 activates retinoic acid recept or-related orphan receptor alpha (RORA) and exhibits potent antiarthri tic activity. Both receptors belong to the superfamily of nuclear rece ptors and are structurally related transcription factors. We tested BR L 49653 and CGP 52608 for receptor specificity on PPAR gamma, RORA, an d retinoic acid receptor oc, a closely related receptor to RORA, and c ompared their pharmacological properties in in vitro and in vivo model s in which these compounds have shown typical effects. BRL 49653 speci fically induced PPAR gamma-mediated gene activation, whereas CGP 52608 specifically activated RORA in transiently transfected cells. Both co mpounds were active in nanomolar concentrations. Leptin production in differentiated adipocytes was inhibited by nanomolar concentrations of BRL. 49653 but not by CGP 52608. BRL 49653 antagonized weight loss, e levated blood glucose levels, and elevated plasma triglyceride levels in an in vivo model of glucocorticoid-induced insulin resistance in ra ts, whereas CGP 52608 exhibited steroid-like effects on triglyceride l evels and body weight in this model. In contrast, potent antiarthritic activity in rat adjuvant arthritis was shown for CGP 52608, whereas B RL 49653 was nearly inactive. Our results support the concept that tra nscriptional control mechanisms via the nuclear receptors PPAR gamma a nd RORA are responsible at least in part for the different pharmacolog ical properties of BRL 49653 and CGP 52608. Both compounds are prototy pes of interesting novel therapeutic agents for the treatment of non-i nsulin-dependent diabetes mellitus and rheumatoid arthritis.