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Detecting Estrogenic Ligands in Personal Care Products using a Yeast Estrogen Screen Optimized for the Undergraduate Teaching Laboratory
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Molecular determinants of tissue selectivity in estrogen receptor modulators

T A Grese1, J P Sluka, H U Bryant

  • 1Endocrine Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. grese@lilly.com

Proceedings of the National Academy of Sciences of the United States of America
|February 12, 1998
PubMed

Insights

Structural differences in estrogen receptor modulators like raloxifene and tamoxifen dictate their tissue-specific effects. These differences in conformation explain why raloxifene and tamoxifen impact uterine tissue differently, offering insights into selective estrogen receptor modulator (SERM) action.

Area of Science:

  • Endocrinology
  • Molecular Pharmacology
  • Medicinal Chemistry

Background:

  • Estrogen receptor (ER) ligand interactions with DNA regulate gene transcription, influencing tissue-specific outcomes.
  • Selective estrogen receptor modulators (SERMs) like raloxifene and tamoxifen exhibit tissue-specific agonist/antagonist effects.
  • Raloxifene and tamoxifen antagonize mammary tissue but are agonists in bone, with tamoxifen uniquely stimulating uterine tissue.

Purpose of the Study:

  • To investigate how structural differences between raloxifene and tamoxifen influence ER/ligand complex conformations.
  • To determine if these conformational changes explain the differential modulation of estrogen-responsive genes and tissue-selective effects, particularly in the uterus.

Main Methods:

  • Synthesis of raloxifene analogs designed to isolate specific structural differences (phenolic hydroxyls, amine substituents, benzothiophene framework, hinge region).
  • Evaluation of these analogs using in vitro and in vivo assays to assess their biological activity.
  • Development of a pharmacophore model based on experimental data.

Main Results:

  • Structural variations significantly alter ER/ligand complex conformations.
  • A pharmacophore model identified a low-energy conformational preference in raloxifene, characterized by an orthogonal orientation of the basic side chain relative to the stilbene plane.
  • This specific conformation, influenced by a hinge region carbon atom, is responsible for raloxifene's lack of uterine stimulation compared to tamoxifen.

Conclusions:

  • Discrete ligand conformations are critical determinants of tissue-selective actions for SERMs.
  • The study elucidates the structural basis for the differential effects of benzothiophene and triarylethylene SERMs on uterine tissue.
  • This understanding facilitates the design of novel SERMs with tailored tissue-specific pharmacological profiles.

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