A-C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions.

Autor: Hanson AM; Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States., Perera KLIS; Department of Chemistry , Marquette University , P.O. Box 1881, Milwaukee , Wisconsin 53201-1881 , United States., Kim J; Department of Psychology , University of Wisconsin-Milwaukee , 2441 East Hartford Avenue , Milwaukee , Wisconsin 53211 , United States., Pandey RK; Department of Chemistry , Marquette University , P.O. Box 1881, Milwaukee , Wisconsin 53201-1881 , United States., Sweeney N; Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States., Lu X; Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States., Imhoff A; Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States., Mackinnon AC; Department of Pathology , Medical College of Wisconsin , 9200 West Wisconsin Avenue , Milwaukee , Wisconsin 53226 , United States., Wargolet AJ; Department of Natural Science , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States., Van Hart RM; Department of Natural Science , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States., Frick KM; Department of Psychology , University of Wisconsin-Milwaukee , 2441 East Hartford Avenue , Milwaukee , Wisconsin 53211 , United States., Donaldson WA; Department of Chemistry , Marquette University , P.O. Box 1881, Milwaukee , Wisconsin 53201-1881 , United States., Sem DS; Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2018 Jun 14; Vol. 61 (11), pp. 4720-4738. Date of Electronic Publication: 2018 Jun 04.
DOI: 10.1021/acs.jmedchem.7b01601
Abstrakt: 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 EC 50 s 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.
Databáze: MEDLINE
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