Determinants of Retinoid X Receptor Transcriptional Antagonism (original) (raw)

2004, Journal of Medicinal Chemistry

The synthesis and bioactivity of the retinoid X receptor (RXR) antagonist 4-[(3′-n-butyl-5′,6′,7′,8′tetrahydro-5′,5′,8′,8′-tetramethyl-2′-naphthalenyl)(cyclopropylidene)methyl]benzoic acid and several heteroatom-substituted analogues are described. Ligand design was based on the scaffold of the 3′-methyl RXR-selective agonist analogue and reports that 3′-n-propyl and longer n-alkyl groups conferred RXR antagonism. The transcriptional antagonism of the 3′-n-butyl analogue was demonstrated by its blockade of retinoic acid receptor (RAR) expression induced by the RXRR/peroxisome proliferator-activated receptor (PPAR) γ heterodimer complexed with an RXRR agonist plus the PPARγ agonist ciglitazone and the inhibition of 9-cis-RA-induced coactivator SRC-1a recruitment to RXRR. Receptor-ligand docking studies using full-atom flexible ligand and flexible receptor suggested that binding of the antagonist to the RXRR antagonist conformation was favored because the salt bridge that formed between the retinoid carboxylate and the RXRR helix H5 arginine-321 was far stronger than that formed on its binding to the agonist conformation. The antagonist also blocked activation of RAR subtypes R and by 9-cis-RA but not that of RARγ. 4365 H NMR δ 0.76 (t, J ) 7.3 Hz, 3H, 4′′-CH3), 1.17 (m, 2H, 3′′-CH2), 1.28 (s, 6H, CH3), 1.31 (m, 2H, 2′′-CH2), 1.32 (s, 6H, CH3), 1.71 (s, 4H, 6′,7′-CH2), 2.25 (t, J ) 8.0 Hz, 2H, 1′′-CH2), 3.91 (s, 3H, OCH3), 5.31 (d, J ) 1.4 Hz, 1H, CdCH), 5.81 (d, J ) 1.4 Hz, 1H, CdCH), 7.09 and 7.10 (2 s, 2H, 1′,4′-NapH), 7.35 (dd, J ) 1.5, 8.2 Hz, 2H, 3,5-ArH), 7.95 ppm (dd, J ) 1.5, 8.1 Hz, 2H, 2,6-ArH).