Retinoid receptor subtype-selective modulators through synthetic modifications of RARγ agonists

A series of retinoids designed to interfere with the repositioning of H12 have been synthesized to identify novel RARγ antagonists based on the structure of known RARγ agonists. The transcriptional activities of the novel ligands were revealed by cell-based reporting assays, using engineered cells containg RAR subtype-selective fusions of the RAR ligand-binding domains with the yeast GAL4 activator DNA-binding domain and the cognate luciferase reporter gene. Whereas none of the ligands exhibited features of a selective RARγ antagonist, some of them are endowed with interesting activities. In particular 24a acts as a pan-RAR agonist that induces at high concentration a higher transactivation potential on RARα than TTNPB and synergizes at low concentration with TTNPB-bound RARα but not RARβ or RARγ. Similarly, 24c synergizes with TTNPB-bound RARγ and exhibits RARα,β antagonist activity. Compounds 24b and 25b are strong RARα,β-selective antagonists without agonist or antagonist activities for RARγ. Compounds 24b and 24c display weak RXR antagonist activity. In addition several pan-antagonists and partial agonist/antagonists have been defined.

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