Estrogen level decreases in post-menopausal women have been shown to increase the risk of memory loss and Alzheimer?s disease. While these effects might be mitigated using hormone replacement therapy, traditional estrogen-based hormone therapies also lead to increased risk of cancer, heart disease and stroke. These adverse effects are mediated predominantly by estrogen receptor-alpha (ER?). Relevant to menopause, aging significantly reduces levels of ER??and ER??in the hippocampus, suggesting an association with age-related memory decline; but, ER??remains the predominant isoform. We hypothesize that an optimal treatment for age-related memory decline in post-menopausal women may be via treatment that selectively activates hippocampal ER?. Our long-term goal is to develop safer and more selective ER? agonists as therapeutics for treating dementia in post-menopausal women. Our objective is to optimize and characterize a novel class of molecules comprised of a 4-hydroxymethyl- cyclohexane ring tethered to a phenol ring, making it an A-C estrogen that closely resembles the naturally occurring estrogen molecule, but lacking the B and D rings. The rationale for the proposed research is that it will provide essential foundational knowledge about estrogenic regulation of cognition that will advance the development of novel treatments; and, it will provide mechanistic insights into the remarkable ER? selectivity that can be achieved with simplified versions of the estrogen itself.
Our Aims Are to: ? Aim 1. Characterize and optimize the structural features of ISP358-2 that are responsible for its high ER? selectivity. We will use docking to guide design and optimization of ISP358-2 based on activity in cell-based (ER? vs. ER? agonist activity) assays, and then demonstrate in vivo efficacy for memory consolidation. ? Aim 2. Determine mechanism of ISP538-2 ER? agonist selectivity. We will measure and characterize ability of optimized ISP358-2 and control (PPT, E2) compounds to cause agonist conformational changes needed to recruit brain-relevant coactivator, thereby inducing transcription. ? Aim 3. Establish the therapeutic potential of the optimized ISP358-2 lead molecule by determining the neural mechanism through which it enhances memory consolidation. We will use intracranial infusions to measure the extent to which ISP358-2 acts like an ER agonist to trigger rapid cell signaling, alter hippocampal morphology, and enhance memory.
This study will produce and provide mechanism for a new class of potent and selective agonists of the human estrogen receptor, beta isoform (ER?), as drug leads and as pharmacological probes of ER? function in vivo. The role of ER? in central nervous system (CNS) function in post- menopausal women is poorly understood; yet, ER? agonists are actively being pursued as new treatments for depression, anxiety and cognitive decline due to low estrogen levels. This new class of compounds may provide therapeutic interventions that lack the carcinogenic potential of ER? agonists, and provide tools to increase our understanding of ER??s role in CNS function.
| Sweeney, Noreena L; Lipker, Lauren; Hanson, Alicia M et al. (2017) Docking into Mycobacterium tuberculosis Thioredoxin Reductase Protein Yields Pyrazolone Lead Molecules for Methicillin-Resistant Staphylococcus aureus. Antibiotics (Basel) 6: |
