A family of novel benzothiophene selective estrogen receptor modulators (BT-SERMs) was synthesized.  Their structure-activity relationships for neuroprotection displayed a spectrum of ERa and ER� binding affinity and agonist/antagonist activity, thus leading to discovery of a neuroprotective pharmacophore that is present in the clinically relevant SERMs, raloxifene, and desmethylarzoxifene (DMA).  The 2-(4'-hydroxyphenyl)-benzo<b>thiophen-6-ol core (BTC) is readily oxidized to a diquinone methide that acts as a Michael acceptor toward cysteine, while the derivatives lacking 4'-hydroxyl group in the 2-phenyl substituent cannot undergo bioactivation to diquinone methides, which indicates that the receptor mediating neuroprotective activity of BT-SERMs could potentially be activated by Michael addition or, alternatively, by simple noncovalent binding.  Collective evidence suggests that the activity of neuroprotective BT-SERMs is GPR30-dependent and ER-independent, and not mediated by antioxidant effects. Comparison of novel BT-SERM derivatives and analogues identified a neuroprotective pharmacophore applicable for design of novel neuroprotective agents with a spectrum of ER activity.

Synthesis of novel benzothiophene selective estrogen receptor modulators (BT-SERMs) that provide neuroprotection by a novel GPR30-dependent mechanism

242nd National Meeting (2011)

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