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Determinants of Retinoid X Receptor Transcriptional Antagonism Claudio N. Cavasotto,| Gang Liu, Sharon Y. James, Peter D. Hobbs, Valerie J. Peterson,#
 

Summary: Articles
Determinants of Retinoid X Receptor Transcriptional Antagonism
Claudio N. Cavasotto,| Gang Liu, Sharon Y. James, Peter D. Hobbs, Valerie J. Peterson,#
Ananyo A. Bhattacharya, Siva K. Kolluri, Xiao-kun Zhang, Mark Leid,# Ruben Abagyan,
Robert C. Liddington, and Marcia I. Dawson*,
Cancer Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, Molsoft L.L.C.,
3366 North Torrey Pines Court, Suite 300, La Jolla, California 92037, Retinoid Program, SRI International,
333 Ravenswood Avenue, Menlo Park, California 94025, College of Pharmacy, Oregon State University,
Corvallis, Oregon 97331, and The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received December 31, 2003
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) heterodimer complexed with an
RXRR agonist plus the PPAR 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

  

Source: Abagyan, Ruben - School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego

 

Collections: Biology and Medicine