A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice.

Journal of Lipid Research
Chelsea DeLeonChristopher K Arnatt

Abstract

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in...Continue Reading

References

Aug 30, 1994·Proceedings of the National Academy of Sciences of the United States of America·S M AronicaB S Katzenellenbogen
Oct 8, 1999·Trends in Endocrinology and Metabolism : TEM·M J Kelly, E J Wagner
Sep 25, 2001·Journal of Applied Physiology·E R Levin
Oct 3, 2001·Physiological Reviews·S NilssonJ A Gustafsson
Mar 3, 2004·Molecular Interventions·Jason Matthews, Jan-Ake Gustafsson
Jul 10, 2004·Essays in Biochemistry·Raj KumarE Brad Thompson
Jan 20, 2005·JAMA : the Journal of the American Medical Association·Dominic J CirilloJoseph C Larson
Feb 12, 2005·Science·Chetana M RevankarEric R Prossnitz
Mar 8, 2006·Nature Chemical Biology·Cristian G BologaEric R Prossnitz
Nov 30, 2006·Pharmacological Reviews·Karin Dahlman-WrightJan-Ake Gustafsson
Jul 7, 2007·Physiological Reviews·Nina HeldringJan-Ake Gustafsson
Mar 29, 2008·Current Genomics·Maria MarinoPaolo Ascenzi
May 12, 2009·Nature Chemical Biology·Megan K DennisEric R Prossnitz
Mar 30, 2010·Journal of Medicinal Chemistry·Caterina BissantzMartin Stahl
Mar 24, 2011·Future Medicinal Chemistry·Jonathan B Baell
Jul 26, 2011·The Journal of Steroid Biochemistry and Molecular Biology·Megan K DennisEric R Prossnitz
Jan 19, 2012·Breast Cancer Research : BCR·Rosamaria LappanoMarcello Maggiolini
Mar 15, 2012·Current Cancer Drug Targets·R LappanoM Maggiolini
May 12, 2012·World Journal of Gastrointestinal Pharmacology and Therapeutics·Piero PortincasaDavid Qh Wang
Oct 12, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Andrés E ZucchettiEnrique J Sánchez Pozzi
Jul 18, 2015·Disease Models & Mechanisms·Rosamaria LappanoMarcello Maggiolini
Aug 26, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Aldo Moreno-UlloaFrancisco Villarreal
Sep 25, 2015·Organic & Biomolecular Chemistry·T PapaliaP Bonaccorsi
Nov 18, 2015·The AAPS Journal·Camillo RosanoRosamaria Lappano
Nov 26, 2015·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·H H WangD Q-H Wang
Mar 26, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Helen H WangDavid Q-H Wang
Dec 22, 2017·Current Opinion in Gastroenterology·Tony Y WangDavid Q-H Wang
Sep 28, 2018·ACS Medicinal Chemistry Letters·Austin O'DeaChristopher Kent Arnatt

❮ Previous
Next ❯

Citations

Nov 10, 2020·Journal of Biomolecular Structure & Dynamics·Shafi Ullah KhanThet Thet Htar
Dec 8, 2020·Frontiers in Endocrinology·Chelsea DeLeonChristopher K Arnatt
Dec 18, 2020·Frontiers in Endocrinology·Milad RouhimoghadamEdward J Filardo
Feb 13, 2021·Frontiers in Endocrinology·Nicolas ChevalierPatrick Fenichel
Jul 24, 2021·European Journal of Pharmacology·Shaojie YangGuoqi Zhu
Jul 26, 2021·European Journal of Pharmacology·Swarne EK L Krishna

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.