Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity

J Med Chem. 1993 Sep 3;36(18):2605-13. doi: 10.1021/jm00070a003.


A major challenge is the development of retinoids with selective biological activities. Recently, studies on retinoid response mechanisms indicate that retinoids activate two classes of nuclear receptor proteins, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Here, we analyze the activity of a series of (E)- and (Z)-stilbenecarboxylic acids for gene transcriptional activation of the RARs and RXR-alpha to determine the optimum pharmacophore for receptor activation. The data obtained indicate that RAR and RXR response pathways can be separated by using the appropriate ligand. The conformations of (Z)-4-[2-(5-,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prop en-1-yl]benzoic acid (Z)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propen-2-yl]benzoic acid were examined by experimental and theoretical methods to establish the appropriate conformation of the latter that specifically activated the retinoid RXR. A palladium(0)-catalyzed aryl bromide-arylboronic acid coupling under nonanhydrous conditions was used to construct a biaryl bond in the conformationally restricted retinoid 2'- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaleny)biphenyl-4-c arboxylic acid, which had RXR activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • Cell Line
  • Computer Simulation
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Receptors, Retinoic Acid*
  • Retinoid X Receptors
  • Retinoids / chemical synthesis
  • Retinoids / chemistry*
  • Retinoids / pharmacology
  • Stilbenes / chemistry*
  • Stilbenes / pharmacology
  • Structure-Activity Relationship
  • Transcription Factors*
  • Transcription, Genetic / drug effects
  • Transcriptional Activation
  • Transfection
  • X-Ray Diffraction


  • Carboxylic Acids
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Retinoids
  • Stilbenes
  • Transcription Factors