A-C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions. J Med Chem 2018 Jun 14;61(11):4720-4738
Date
05/10/2018Pubmed ID
29741891Pubmed Central ID
PMC7217030DOI
10.1021/acs.jmedchem.7b01601Scopus ID
2-s2.0-85046950983 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC50s of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.
Author List
Hanson AM, Perera KLIS, Kim J, Pandey RK, Sweeney N, Lu X, Imhoff A, Mackinnon AC, Wargolet AJ, Van Hart RM, Frick KM, Donaldson WA, Sem DSAuthors
William Donaldson PhD Professor in the Department of Chemistry department at Marquette UniversityKaryn Frick BA,MA,PhD Professor in the Psychology department at University of Wisconsin - Milwaukee
MESH terms used to index this publication - Major topics in bold
Cytochrome P-450 Enzyme SystemDose-Response Relationship, Drug
Estrogen Receptor beta
Estrogens
Humans
MCF-7 Cells
Memory Consolidation
Molecular Docking Simulation
Protein Conformation
Structure-Activity Relationship
