Neurotrophic estrogens: essential profile and endpoints for drug discovery.
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.
Patchev
Vladimir K
VK
Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany. Vladimir.Patchev@bayerhealthcare.com
Bachurin
Sergey O
SO
Albers
Michael
M
Fritzemeier
Karl-Heinrich
KH
Papadopoulos
Vassilios
V
D000818:Animals; D001519:Behavior / Q000187:drug effects; D002491:Central Nervous System Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D023381:Endpoint Determination; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans
D002491:Central Nervous System Agents; D004967:Estrogens