Estrogen receptor binding and estrogenic/antiestrogenic effects of two new metabolites of nitromiphene, 2-[p-[2-nitro-1-(4-methoxyphenyl)-2-phenylvinyl]phenoxy]-N-ethylpyrrolidine

Reduction of the triarylethylene antiestrogen 2-[p-[2-nitro-1-(4-methoxphenyl)-2-phenylvinyl]phenoxy]-N-ethylpyrrolidine (1) with sodium borohydride-stannous chloride afforded 2-(p-methoxyphenyl)-p'-(2-pyrrolidin-1-ylethoxy)deoxybenzoin (2). Incubation of 1 with rat cecal content suspension under aerobic or anaerobic conditions also resulted in the generation of 2. The lactam analogue of 1 (6) was prepared by condensation of 4-(2-bromoethoxy)-4'-methoxybenzophenone (3) with benzylmagnesium chloride, followed by dehydration, amidation with 2-pyrrolidinone, and nitration. A metabolite with chromatographic and spectral properties identical with those of 6 was found in extracts from incubation mixtures of 1 with phenobarbital-induced rat liver 9000g supernatant. Compound 2 did not exhibit appreciable binding to the rat uterine cytosol estrogen receptor at concentrations of up to 1 X 10(-6) M and had no estrogenic or antiestrogenic activity in the 3-day rat uterotropic assay. By contrast, 6 had estrogen receptor affinity somewhat greater than that of 1 and slightly greater estrogenic activity accompanied by reduced antiestrogenic activity in comparison with those of 1.