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Published on: August 13, 2019
Neurotrophic estrogens: essential profile and endpoints for drug discovery
Vladimir K Patchev1, Sergey O Bachurin, Michael Albers
1Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany. Vladimir.Patchev@bayerhealthcare.com
Abstract:
Criteria for the early recognition of selective neurotrophic action are crucial for the discovery of estrogens for supplementation therapy. The comparative characterization of 'tool' compounds in different paradigms demonstrates that estrogen-mediated CNS effects are discernible before the manifestation of changes in primary target organs. Agonist activity at, and recruitment of the coactivator SRC-1 by, the estrogen receptor alpha accurately reflect peripheral, but not neurotrophic, efficacy. Interaction with, and SRC-1 recruitment at, the estrogen receptor beta appears to be an essential prerequisite for pronounced CNS effects. Monitoring of the hypothalamo-pituitary-adrenal axis activity and the differential organ-specific induction of estrogen-responsive proteins are helpful for early delineation of CNS efficacy. Behavioral and antioxidant efficacy are useful confirmatory readouts, with limited roles in lead selection. Finally, an algorithm for the identification of estrogens with a neurotrophic profile can be generated by assigning 'performance grades' in a multifarious test array.
Insights
Identifying estrogens with neurotrophic effects requires specific criteria. Estrogen receptor beta interactions are key for central nervous system (CNS) efficacy, distinct from peripheral actions, aiding therapeutic discovery.
Area of Science:
- Endocrinology
- Neuroscience
- Pharmacology
Background:
- Selective neurotrophic action is crucial for discovering new estrogen therapies.
- Estrogen's central nervous system (CNS) effects can be observed before peripheral target organ changes.
- Estrogen receptor alpha (ERα) and beta (ERβ) signaling pathways have differential roles in efficacy.
Purpose of the Study:
- To establish criteria for early recognition of selective neurotrophic action in estrogens.
- To differentiate between peripheral and CNS-specific estrogenic effects.
- To develop an algorithm for identifying estrogens with neurotrophic potential for supplementation therapy.
Main Methods:
- Comparative characterization of 'tool' compounds across different experimental paradigms.
- Assessing agonist activity and coactivator SRC-1 recruitment at ERα and ERβ.
- Monitoring hypothalamo-pituitary-adrenal (HPA) axis activity and organ-specific estrogen-responsive protein induction.
- Evaluating behavioral and antioxidant efficacy as confirmatory readouts.
Main Results:
- Estrogen receptor alpha (ERα) activity correlates with peripheral efficacy, not neurotrophic effects.
- Estrogen receptor beta (ERβ) interaction and SRC-1 recruitment are prerequisites for significant CNS effects.
- HPA axis monitoring and differential protein induction aid in early CNS efficacy delineation.
- Behavioral and antioxidant assays serve as confirmatory, not primary selection, tools.
Conclusions:
- Estrogen receptor beta (ERβ) is critical for neurotrophic efficacy, differentiating it from ERα-mediated peripheral actions.
- A combination of specific assays, including HPA axis and protein induction, can identify neurotrophic estrogens early.
- An algorithm integrating performance grades from multifarious tests can guide the selection of estrogens for CNS-targeted supplementation therapy.
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