The discovery of tetrahydrofluorenones as a new class of estrogen receptor β-subtype selective ligands

Estrogen receptor (ER) subtype agonists alter monoamine levels in the female rat brain

“…PPT both increased uterine weight and maintained body weight at a level similar to E, which is consistent with the idea that the ER␣ plays the predominant role in uterine proliferation and maintenance of body weight [63]. The ER␤ agonist C19 is a novel non-steroidal ligand that has low nM affinity for the ER␤ and is >70-fold selective for ER␤ compared to the ER␣ [39]. The fact that the ER␤ ligand had no effect on uterine or body weight but affected levels of neurotransmitters supports the idea that the dose was sufficient to selectively activate the ER␤.…”

“…The ER␤ agonist C19 has a potency of 1.8 nM on human ER␤ which is similar to that of E, but C19 is >70-fold selective for the ER␤ compared to ER␣ [39]. The dose of the ER␤ agonist was based on unpublished data (Merck Research Labs) on the effect of this compound on immature rat uterine weight.…”

“…Animals were weighed, assigned to treatment groups (n = 8/group) and dosed s.c. once daily for 4 days with vehicle (100 l; sesame oil, Sigma, St. Louis, MO), 17␤-estradiol (E, 0.05 mg/kg, Sigma), an ER␤ subtype-selective agonist (4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one referred to as C19; 3 mg/kg; [39]) or an ER␣ subtype-selective agonist (4,4 ,4 -(4-propyl-{1H}-pyrazole-1,3,5-triyl)trisphenol (PPT); 3 mg/kg; Tocris Cookson, Inc., St. Louis, MO, Catalog #1426). The ER␤ agonist C19 has a potency of 1.8 nM on human ER␤ which is similar to that of E, but C19 is >70-fold selective for the ER␤ compared to ER␣ [39].…”

Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test

“…Some of these include caffeic acid phenethyl ester (Jung et al, 2010), butyl 4-(butyryloxy) benzoate (Lin et al, 2008), the diarylpropionitriles (Meyers et al, 2001), the aryl diphenolic azoles and the benzoazole ERB-041 (Malamas et al, 2004;Follettie et al, 2006), genistein derivatives (Mewshaw et al, 2005), effusol derivatives (e.g., benzo[c]chromenone analogs) (Sun et al, 2006), salicylaldoximes (Bertini et al, 2011) and the tetrahydrofluorenones (Parker et al, 2006;Wilkening et al, 2006).…”

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

“…It is currently known that the most important ERb agonists usually show two H-bonds with the receptor binding site, one with H475 and one with the E305-R346 network system. The analysis of the available ERb crystal structures confirmed these data, as only one ligand (2GIU PDB code 37 ) did not show these two H-bonds. On these bases, as a first step of the virtual screening workflow ( Figure 5), a constrained docking evaluation was applied.…”