ABSTRACT
A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
Subject(s)
Benzopyrans/chemical synthesis , Estrogen Antagonists/chemical synthesis , Hot Flashes/drug therapy , Naphthalenes/chemical synthesis , Selective Estrogen Receptor Modulators/chemical synthesis , Adenocarcinoma , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Benzopyrans/chemistry , Benzopyrans/pharmacology , Bone Density/drug effects , Breast Neoplasms , Cell Line, Tumor , Cell Proliferation/drug effects , Cholesterol/blood , Estrogen Antagonists/chemistry , Estrogen Antagonists/pharmacology , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Female , Humans , Morphine/pharmacology , Naphthalenes/chemistry , Naphthalenes/pharmacology , Ovariectomy , Rats , Rats, Sprague-Dawley , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Stereoisomerism , Uterine Neoplasms , Uterus/drug effects , Uterus/growth & developmentABSTRACT
A new series of estrogen receptor ligands based on a 6-hydroxy-tetrahydroquinoline scaffold is described, in addition to their binding affinity and functional activity in MCF-7 cells. Several 1,2-disubstituted tetrahydroquinolines bearing a basic side chain were shown to be high affinity ligands and antagonists in the MCF-7 proliferation assay. Compounds lacking the basic side chain were agonists in the MCF-7 assay.
