Synthesis and biological evaluation of SERMs with potent nongenomic estrogenic activity.
We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ERalpha and ERbeta). These compounds are analogues of 4-hydroxytamoxifen, but unlike 4-hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER-mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST-X, elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic gamma-aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST-X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.
Tobias
Sandra C
SC
Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, CA 94143-2280, USA.
Qiu
Jian
J
Kelly
Martin J
MJ
Scanlan
Thomas S
TS
D004967:Estrogens / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*
D004967:Estrogens; D020845:Selective Estrogen Receptor Modulators