Antagonists Selective for Estrogen Receptor α

Abstract

To develop compounds that are antagonists on ER(alpha), but not ER(beta), we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ER(alpha) than to ER(beta). In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ER(alpha). These BSC-pyrazoles are themselves inactive on ER(alpha) and ER(beta), and they antagonize E2 stimulation by ER(alpha) only. We investigated seven basic side-chain substituents on various alkyl-triaryl-substituted pyrazoles, and the most ER(alpha)-selective compound was methyl-piperidino-pyrazole (MPP). ER(alpha)-selective antagonism was observed on diverse reporter-promoter gene constructs containing estrogen response elements that are consensus, nonconsensus (pS2), or comprised of multiple half-estrogen response elements (NHERF/EBP50) and on genes in which ER works indirectly by tethering to other DNA-bound proteins (TGF(beta)3). In contrast to these BSC-pyrazoles, the antiestrogens trans-hydroxytamoxifen, raloxifene, and ICI 182,780 suppress E2 activity via both ER(alpha) and ER(beta). The most effective BSC-pyrazole, MPP, fully antagonized E2 stimulation of pS2 mRNA in MCF-7 breast cancer cells, consistent with the fact that these cells contain almost exclusively ER(alpha). These compounds should be useful in studying the biological functions of ER(alpha) and ER(beta) and in selectively blocking responses that are mediated through ER(alpha).

Estrogen Receptor .ALPHA. Regulates Insulin Sensitivity through IRS-1 Tyrosine Phosphorylation in Mature 3T3-L1 Adipocytes

“…This observation suggests that ER-α plays a crucial role in maintaining insulin-stimulated glucose uptake during treatment with a relatively low concentration of E2 in mature adipocytes. Unfortunately, the effect of MPP on cells treated with a high concentration of E2 could not be examined, because such an experiment would require a very high concentration of MPP, a competitive antagonist of ER-α [14]. In our 3T3-L1 adipocytes, treatment with PPT produced biphasic effects on insulin stimulated glucose uptake as was observed with E2 treatment.…”

“…Propylpyrazole triol (PPT), a member of the triarylpyrazole class, is more than 10,000-fold more potent on ER-α than on ER-β [12,13]. Recently, Katzenellenbogen et al developed a compound known to antagonize ER-α, but not ER-β, by adding basic side-chains typically found in non steroidal anti-estrogens to pyrazole compounds, and this specific antagonist was named methylpiperidino-pyrazole (MPP) [14]. These compounds would presumably be useful for studying the functions of ER-α in adipocytes.…”

Regulation of bovine oviductal NO synthesis by follicular steroids and prostaglandins

“…MPP dihydrochloride (100 nmol/L, M7068; Sigma-Aldrich) for ESR1 and PHTPP (100 nmol/L, 2662; R&D Systems) for ESR2 were used as selective antagonists. MPP dihydrochloride has been demonstrated to be a selective antagonist for ESR1 (Sun et al 2002) and PHTPP is known to display 36-fold selectivity for ESR2 than ESR1 (Compton et al 2004). Antagonists of PTGER2 or PTGER4 were incubated in combination with PGE2 (1 μmol/L) in cultured ampullary epithelial cells.…”

Effects of Short-Term Treatment with Estrogen Receptor Agonist on Morphological Changes in Reproductive Organs of Adult Male Mice

“…ICI 182,780 (ICI) is a well-established ER antagonist (Cho et al, 2003;Oliveira et al, 2002Oliveira et al, , 2003, whereas propyl pyrazole triol (PPT) is an ERα-specific agonist. The affinity of PPT for ERα has been reported to be at least 410 to 1,000 times higher compared with ERβ (Harris et al, 2002;Stauffer et al, 2000;Sun et al, 2002). ICI and PPT have been used for investigating estrogen function in male reproductive organs.…”