Carboxylic acid analogues of tamoxifen: (Z)-2-[p-(1, 2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine. Estrogen receptor affinity and estrogen antagonist effects in MCF-7 cells.

The triarylethylene estrogen mimetic (E, Z)-4-[1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxyacetic acid (4) represents a novel class of estrogen receptor (ER) ligands which, like tamoxifen (1), can elicit estrogen agonist and antagonist effects, in turn, in nonreproductive and reproductive tissues. Analogues of 4, incorporating structural features shown previously in triarylethylenes to improve ER affinity and estrogen antagonist properties, were prepared with the ultimate aim of identifying substances with improved estrogenicity exclusive of reproductive tissues. Thus, the side chain of 4 was elongated to give oxybutyric acid 13, which was further altered by (a) repositioning of its p-hydroxyl to the neighboring m-position (12) and (b) ethylenic bond reduction (14). Also, the p-hydroxyl group and oxyacetic acid groups of 4 were, in turn, shifted to the neighboring m-positions, affording 8 and 9. Oxybutyric acid analogue 13 had about 2 times the affinity for human ERalpha as 4, and its antiproliferative effect in MCF-7 cells was greater than that of 1. Dihydro analogue 14, which was conformationally similar to cis-13, had very low ER affinity and antiestrogenicity, and m-hydroxy analogue 12 also had reduced ER affinity and potency, but its MCF-7 cell antiproliferative efficacy was retained. Modest ER affinity and antiproliferative potency were seen with 8, in which phenolic and phenyl rings were trans to one another, but 9, in which these rings were cis, was inactive. Our findings indicate that two-carbon side-chain elongation and/or m-positioning of the hydroxyl group in 4 affords analogues with dominant estrogen antagonist effects in MCF-7 cells.

Estrogenic tamoxifen derivatives: categorization of intrinsic estrogenicity in MCF-7 cells.

Triarylethylenes bearing acetic acid side chains, exemplified by 4-[1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxyacetic acid (4HTA), a derivative of tamoxifen (TAM), are of current interest as estrogen mimics lacking reproductive tract effects. Affinities for estrogen receptors (ER) and effects on cell growth kinetics of a diverse series of such compounds were compared with 4HTA, TAM, and with standard estrogens 17beta-estradiol (E2) and chlorotrianisene (CTA) in MCF-7 cells. These compounds exhibited concentration dependent cell growth stimulation comparable to that of CTA but less than that of E2. Growth stimulation of the more potent compounds was antagonized by TAM, signifying that effects were mediated via interaction with ER. At concentrations of 1 microM or higher, compounds with efficacies less than that of E2 were weak antagonists of estradiol-stimulated growth. Both intracellular ER affinities and growth rate stimulation potencies of the triarylethylene acetic acids and the standard ER ligands varied over a range of nearly three orders of magnitude. Analysis of growth stimulatory potency as a function of ER affinity revealed dual parallel correlations: the potency/ER affinity ratios of 4HTA and four of its analogues was about 100-fold less than those of the hydroxytriarylethane and bisphenolic analogs and the three standard ER ligands. These results suggested that ER liganded with the latter substances is more 'effective' at nuclear effector sites than is ER liganded with 4HTA and the other acidic triarylethylenes.

Reduced beta-endorphin secretion in young patients with mild essential hypertension at rest and during exercise.

Evidence suggests that altered central adrenergic and opioidergic activities are involved in the elevated blood pressure of patients with essential hypertension. In the present study plasma concentrations of the opioid peptide beta-endorphin were significantly lower at rest in young subjects with essential hypertension and high plasma noradrenaline (n = 9) than in normotensive controls (n = 13, P less than 0.05). After bicycle exercise the beta-endorphin of both groups increased comparably, the percentage increase being greater in essential hypertensives than in controls. Treatment with clonidine for 14 days normalized low beta-endorphin, high plasma noradrenaline and high blood pressure in essential hypertensives at rest, but had no effect in controls. After bicycle exercise clonidine induced a threefold greater increase in beta-endorphin in controls than in essential hypertensives. The results point to a reduced endorphinergic activity in essential hypertensives, both at rest and during exercise, which can be normalized by central alpha 2-agonism at rest only. The results may indicate altered interactions between central adrenergic and opioidergic receptor systems, which could contribute to high blood pressure in essential hypertensives.