Estrogen Antagonists in Chick Oviduct: Antagonist Activity of Eight Synthetic Triphenylethylene Derivatives and Their Interactions with Cytoplasmic and Nuclear Estrogen Receptors

Abstract

The estrogen agonist and antagonist activities of eight structurally related synthetic compounds [trans-l-(4β-dimethylaminoethoxyphenyl) l,2-diphenylbut-l-ene (tamoxifen) cis-1- (4β-dimethylaminoethoxyphenyl) 1,2-diphenylbut-l-ene (ICI 47,699), α-(4-pyrrolidinoethoxy)phenyl-4-methoxy-α-nitrostilbene (CI 628), a-(4-dimethylaminopropoxy)phenyl-4-methoxy- a-nitrostilbene citrate (CI 680), l-(2-[p-(3,4-dihydro-6-methoxy- 2-pheny1-1-naphthyl)phenoxy]ethyl)pyrrolidine hydrochloride (nafoxidine), cis(3-[p-1,2,3,4-tetrahydro-6-methoxy-2- pheny1-1-naphthyl)phenoxy]l,2-propanediol (U 23,469) trans-1- (p-β-diethy laminoethoxyphenyl) 1,2- diphenyl - 2 - chloroethylene monocitrate (enclomiphene), and cts-l-(p-β-diethylaminoethoxyphenyl) l,2-diphenyl-2-chloroethylene monocitrate (zuclomiphene)] were tested in the estrogen-withdrawn chick oviduct. No compound demonstrated agonist activity, as assessed by changes in oviduct wet weight, DNA,protein, and progesterone receptor concentration, when administered for 1 or 3 days at doses ranging from 0.1-100 mg/kg BW. When 25 mgvkg enclomiphene, tamoxifen, CI 628, CI 680, or nafoxidine were administered together with 5 mg/kg estradiol benzoate, significant inhibition of estrogen-induced increases in oviduct wet weight, DNA, protein, and progesterone receptor concentration was observed 24 h later. ICI 47,699, zuclomiphene, and U 23,469 showed no antagonism at this dose. However, when the cis isomers (ICI 47,699 and zuclomiphene) were administered at a dose of 25 mg/kg-day together with 1 mg/kg-day estradiol benzoate, they both demonstrated significant antagonist activity 3–4 days later. All eight ligands were able to displace tritiated estradiol from its receptor sites in oviduct cytosol and nuclear extracts. The five compounds that were potent antagonists (enclomiphene, CI 628, CI 680, tamoxifen, and nafoxidine) had relative binding affinities (estradiol = 100)for the nuclear estrogen receptor ranging from 10–24%. Within this group, the relative binding affinity was not highly correlated with the degree of antagonism. The weak antagonists (ICI 47,699, zuclomiphene, and U 23,469) had comparatively lower affinities for the estrogen receptor, i.e. 1.0–1.5% that of estradiol. It is concluded that under these experimental conditions, none of the above compounds were estrogenic, and all except U 23,469 showed significant estrogen antagonism.