Estrogen receptor β ligands: Recent advances and biomedical applications

Abstract

Recent work elucidating the role that the estrogen receptor β (ERβ), a member of the nuclear receptor superfamily, plays in regulating various physiological functions has highlighted the potential of this receptor subtype as a therapeutic target for several pathologies. In fact, molecules that are able to selectively activate ERβ hold promise for the treatment of certain cancers, as well as endometriosis, inflammatory diseases including rheumatoid arthritis, and cardiovascular and CNS conditions. Nevertheless, ERβ remains a challenging target because its ligand-binding cavity is very similar to that present in ERα, and this makes it difficult to develop ligands having sufficient levels of ERβ selectivity for therapeutic use. Nevertheless, considerable advances have recently been made in developing both nonsteroidal and steroidal ERβ-selective agonists. These molecules constitute not only important tools to probe the biological effects of the selective stimulation of ERβ, but some of them appear to be agents with considerable therapeutic potential. This study provides a detailed review of selective ERβ ligands that have been developed recently. After a brief introduction to the structure and nature of the two ERs and the biology of ERβ and its isoforms, the ligands are classified on the basis of their structures and activities. Common pharmacophore elements are highlighted throughout the description of the various chemical classes analyzed, and these elements are presented in a concluding summary overview along with a discussion of potential therapeutic applications of these agents in biomedicine.

Synthesis of 2-Phenylbenzofuran Derivatives and Selective Binding Activities on Estrogen Receptor

“…The result was in accordance with ERβ with a smaller ligand binding pocket than ERα suggested by Hubbard and Katzenellenbogen. 24,26,27) The molecule volume of 4g was about 178.0 Å 3 , while 5g was 150.3 Å 3 by calculation. Moreover, compound 5g exhibited more planar profile with ERβ relative to 4g.…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…Because of the rigid (conformationally inflexible) nature of E2 and the requirements of a ligand-binding pocket that recognizes E2, it is perhaps not surprising that GPER exhibits a similar but not identical capacity for "promiscuous" binding to many of the same compounds that bind ERa/b (Lathe and Kotelevtsev, 2014). With the developing recognition of the clinical relevance 516 Prossnitz and Arterburn for ERa/b-selective pharmacologic agents (Minutolo et al, 2011) and the involvement of multiple receptors and pathways in physiologic responses, there is increasing awareness of the importance of evaluating the interactions of these compounds with respect to GPER binding and activity . The issues of receptor selectivity, cross-reactivity, and multiple signaling pathways are intimately connected with the effective concentrations of a compound used to elicit pharmacologic responses, which can result in nonclassic or biphasic dose responses (Calabrese, 2001;Lebedeva et al, 2012).…”

Receptor-based virtual screening evaluation for the identification of estrogen receptorβligands

“…At present, only a limited number of ER agonist showing a remarkable selectivity toward ERb have been reported in the literature. This is due to the fact that the ligand binding domains of the two receptor subtypes are very similar, in spite of a 56% of sequence identity because they have only two pairs of non-conserved residues in their ligand binding pocket 14 . Among the computational studies concerning ER ligands reported so far in the literature, only a small number of virtual screening (VS) procedures have been developed and applied for the search of novel ERb-selective agonists/SERMs.…”