Anti-implantation effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran, a potent antiestrogenic agent in rats

Objective: To investigate the anti-implantation effect and hormonal profile of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran (K-1) in rats. Design: In vivo assays for anti-implantation activity were performed in pregnant rats. Assays for estrogenicity/antiesrogenicity were performed in immature ovariectomized female rats. In vitro competitive binding of K-1 to human recombinant ER alpha, transient transfection assay using ERE-luciferase reporter, and alkaline phosphatase (ALP) activity as a measure of estrogenicity and/antiestrogenicity in human endometrial carcinoma cells were performed. Setting: Research laboratory. Animal(s): Adult female rats for anti-implantation activity, immature ovariectomized female rats, and immature castrated/intact male rats. Intervention(s): None. Main Outcome Measure(s): Number of implantations, uterine growth, luciferase reporter activity, ER binding affinity, and ALP activity. Result(s): Compound K-1 given orally for 1-7 days post coitum at the dose of 100 mu g/kg body weight prevented pregnancy in 100% of rats. K-1 was a potent antiestrogenic, and at 50 mu g/kg, it could inhibit the effect of 1 mu g E-2 in immature rats. Compound was devoid of uterotrophic, androgenic, or antigonadotropic activity. A high affinity binding to ER alpha was displayed by K-1, with a relative binding affinity of 5% of E-2. In human endometrial carcinoma cells, K-1 did not induce ER alpha-mediated transcriptional activation that is measured as luciferase reporter activity. K-1 antagonized the E-induced transcriptional activation significantly. K-1 also antagonized E-induced ALP activity in human endometrial cells. Conclusion(s): K-1 appeared to exert its antifertility action by virtue of its strong antiestrogenic activity. (Fertil Steril (R) 2011;95:1322-7. (C) 2011 by American Society for Reproductive Medicine.)