A-CD Estrogens. I. Substituent Effects, Hormone Potency, and Receptor Subtype Selectivity in a New Family of Flexible Estrogenic Compounds.
Summary of "A-CD Estrogens. I. Substituent Effects, Hormone Potency, and Receptor Subtype Selectivity in a New Family of Flexible Estrogenic Compounds."
Long-term use of estrogen supplements by women leads to an increased risk of breast and uterine cancers. Possible mechanisms include metabolism of estradiol and compounds related to tumor-initiating quinones, and ligand-induced activation of the estrogen receptors ERα and ERβ which can cause cancer cell proliferation, depending on the ratio of receptors present. One therapeutic goal would be to create a spectrum of compounds of variable potency for ERα and ERβ, which are resistant to quinone formation, and to determine an optimum point in this spectrum. We describe the synthesis, modeling, binding affinities, hormone potency, and a measure of quinone formation for a new family of A-CD estrogens, where the A-C bond is formed by ring coupling. Some substituents on the A-ring increase hormone potency, and one compound is much less quinone-forming than estradiol. These compounds span a wide range of receptor subtype selectivities and may be useful in hormone replacement therapy.
Affiliation
Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada.
Journal Details
This article was published in the following journal.
Name: Journal of medicinal chemistry
ISSN: 1520-4804
Pages: 433-48
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21190382
- DOI: http://dx.doi.org/10.1021/jm100513m
Medical and Biotech [MESH] Definitions
Receptor, Parathyroid Hormone, Type 1
A parathyroid hormone receptor subtype that recognizes both PARATHYROID HORMONE and PARATHYROID HORMONE-RELATED PROTEIN. It is a G-protein-coupled receptor that is expressed at high levels in BONE and in KIDNEY.
Receptor, Parathyroid Hormone, Type 2
A parathyroid hormone receptor subtype found in the BRAIN and the PANCREAS. It is a G-protein-coupled receptor with a ligand specificity that varies between homologs from different species.
Receptor, Serotonin, 5-ht2c
A serotonin receptor subtype found primarily in the CENTRAL NERVOUS SYSTEM and the CHOROID PLEXUS. This receptor subtype is believed to mediate the anorectic action of SEROTONIN, while selective antagonists of the 5-HT2C receptor appear to induce ANXIETY. Several isoforms of this receptor subtype exist, due to adenine deaminase editing of the receptor mRNA.
Receptor, Serotonin, 5-ht2a
A serotonin receptor subtype found widely distributed in peripheral tissues where it mediates the contractile responses of variety of tissues that contain SMOOTH MUSCLE. Selective 5-HT2A receptor antagonists include KETANSERIN. The 5-HT2A subtype is also located in BASAL GANGLIA and CEREBRAL CORTEX of the BRAIN where it mediates the effects of HALLUCINOGENS such as LSD.
Receptor, Melanocortin, Type 2
A melanocortin receptor subtype found primarily in the ADRENAL CORTEX. It shows specificity for ADRENOCORTICOTROPIC HORMONE.
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