BINDING CHARACTERISTICS OF NOVEL NONSTEROIDAL ANTIESTROGENS TO THE RAT UTERINE ESTROGEN-RECEPTORS

Tamoxifen (TAM), the only antiestrogen currently available for the end ocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiest rogens to the rat uterine estrogen receptor. As measured by competitio n studies, the affinity of EM-652, the active metabolite of the prodru g EM-800, for the estrogen receptor is 7-11 times higher than that of 17 beta-estradiol (E-2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), t he active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremife ne in displacing [H-3]E-2 from the rat uterine estrogen receptor. On t he other hand, the prodrug EM-800 and Tamoxifen have respectively 150- fold and 410-fold less affinity for the estrogen receptor than the pur e antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM o r OH-TAM was observed to the rat uterine progesterone receptor at conc entrations up to 10 000 nM except for TAM that caused a 50% displaceme nt of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM -800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the h igh affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes th e compound having the highest known affinity for the estrogen receptor . Due to its unique potency and its pure antiestrogenic activity alrea dy demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women. (C) 1998 Else vier Science Ltd. All rights reserved.