Synthesis and biological evaluation of SERMs with potent nongenomic estrogenic activity

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ERα and ERβ). These compounds are analogues of 4-hydroxytamoxifen, but unlike 4-hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER-mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST-X, elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic γ-aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST-X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.

Original languageEnglish (US)
Pages (from-to)565-571
Number of pages7
JournalChemMedChem
Volume1
Issue number5
DOIs
StatePublished - May 2006

Fingerprint

Selective Estrogen Receptor Modulators
Estrogens
Isomers
Estrogen Receptors
Neurons
Aminobutyrates
Pro-Opiomelanocortin
Alkenes
Transcription
Amides
Genes
Chemical activation
afimoxifene

Keywords

  • Estrogen receptors
  • Genomic response
  • GIRK
  • Nongenomic response
  • SERMs

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Synthesis and biological evaluation of SERMs with potent nongenomic estrogenic activity. / Tobias, Sandra C.; Qiu, Jian; Kelly, Martin; Scanlan, Thomas (Tom).

In: ChemMedChem, Vol. 1, No. 5, 05.2006, p. 565-571.

Research output: Contribution to journalArticle

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AU - Qiu, Jian

AU - Kelly, Martin

AU - Scanlan, Thomas (Tom)

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N2 - We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ERα and ERβ). These compounds are analogues of 4-hydroxytamoxifen, but unlike 4-hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER-mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST-X, elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic γ-aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST-X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.

AB - We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ERα and ERβ). These compounds are analogues of 4-hydroxytamoxifen, but unlike 4-hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER-mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST-X, elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic γ-aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST-X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.

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