Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification

Richardson, Timothy I.; Dodge, Jeffrey A.; Durst, Gregory L.; Pfeifer, Lance A.; Shah, Jikesh; Wang, Yong; Durbin, Jim D.; Krishnan, Venkatesh; Norman, Bryan H.

doi:10.1016/j.bmcl.2007.06.052

Cited by 45 publications

(17 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ERβ agonist LY3201, (3aS,4R,9bR)-2,2-difluoro-4-(4-hydroxyphenyl)-3,3a,4,9b-tetrahydro-1H-cyclopenta[c]chromen-8-ol (CAS 787621-78-7), was prepared according to methods previously described (32). This study was conducted in accordance with the University of Houston guidelines on the use of laboratory animals.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Tan

Dai

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβ over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD + terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP + astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERβ was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERβ agonist results in changes opposite to those reported in estradiol-17β-treated mice and suggests that ERα and ERβ play opposing roles in the brain.neurotransmitter | glutamate toxicity | cerebral cortex | hippocampus O f the two estrogen receptors (ERs), ERα appears to be the major player in regulating the reproductive system, whereas both receptors ERα and ERβ are involved in regulation of mood and affective disorders (1, 2). Several studies show that ERα activation is anxiogenic (3-5), whereas ERβ activation is anxiolytic and controls expression of fear and anxiety-like behaviors (6-9). Not surprisingly, estradiol (E2), which binds equally well to ERα and ERβ, has unpredictable effects on abnormal psychiatric behaviors, depending on dose, treatment regimens, or animal models (10-13). In hippocampal cultures both exogenous (E2) treatment and locally synthesized E2 up-regulate ERα and down-regulate ERβ expression (14). Thus, E2 has unpredictable effects on the balance between anxiogenic and anxiolytic effects, in part because E2 has opposite effects on ERα and ERβ (15). Using subtype-selective ligands, we can begin to study the outcome of selective activation or inhibition of a particular receptor subtype involved in different behaviors.Spines and the synapses located on neurons are the sites at which neuronal communication occurs and are essential for complex behavioral phenomena and cognition. In the mature CNS, alterations in synapse structure and function continue to be a dynamic process that is of fundamental importance to learning and memory as well as other adaptive abilities of the brain. Studies...

show abstract

Section: Methodsmentioning

confidence: 99%

“…The ERβ agonist LY3201, (3aS, 4R, 9bR)-2, 2-difluoro-4-(4-hydroxyphenyl)-3, 3a, 4, 9b-tetrahydro-1H-cyclopenta[c]chromen-8-ol (CAS 787621-78-7), was prepared according to methods previously described (32). After exposure to LY3201, a decrease of spines, NMDA receptors (NMDARs) and increase of GAD65+67, astrocytes, and glutamine synthesis (GS) were observed.…”

mentioning

confidence: 99%

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Tan

Dai

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The ERβ agonist LY3201, (3aS, 4R, 9bR)-2, 2-difluoro-4-(4-hydroxyphenyl)-3, 3a, 4, 9b-tetrahydro-1H-cyclopenta[c] chromen-8-ol (CAS 787621-78-7), was prepared as described previously (40). All animals were 8-wk-old SJL/J females, purchased from Jackson Laboratory.…”

Section: Methodsmentioning

confidence: 99%

Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis

Tan

Dai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

View full text Add to dashboard Cite

A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERβ, mediates the beneficial effects in microglia. In this study, we found that ERβ, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERβ agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERβ agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF - κB, as well as the NF-κB–induced gene inducible nitric oxide synthase in microglia and CD3 + T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERβ-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.

show abstract

“…Richardson et al 102 also described the synthesis of cyclohexanones 121a and 121b intermediates for SAR studies of the C-ring on the benzopyran scaffold. …”

Section: Scheme 29mentioning

confidence: 97%

Syntheses and Biological Activities of Chroman-2-ones. A Review

Kamat

Tilve

Kamat

et al. 2015

Organic Preparations and Procedures International

View full text Add to dashboard Cite

Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification

Cited by 45 publications

References 23 publications

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis

Syntheses and Biological Activities of Chroman-2-ones. A Review

Contact Info

Product

Resources

About