NONSTEROIDAL ANTIANDROGENS - SYNTHESIS AND BIOLOGICAL PROFILE OF HIGH-AFFINITY LIGANDS FOR THE ANDROGEN RECEPTOR

New N-substituted arylthiohydantoin antiandrogens were synthesized. Th ese compounds presented exceptionnally high relative binding affinitie s (RBAs) for the rat androgen receptor (AR): up to 3 times that of tes tosterone (T) and 100 times the RBAs of non-steroidal antiandrogens su ch as flutamide, Casodex and Anandron. Furthermore, unlike available m arkers for AR, they were totally devoid of any binding to the other st eroid receptors. RU 59063, the molecule with the highest RBA, was trit iated. When it was compared to [H-3]T for the assay of rat, mouse, ham ster and human AR, it gave rise to the same number of binding sites bu t its K-a (6 x 10(9) M(-1)) for rat and human AR were, respectively 3 and 8 times higher than that of T. Moreover RU 59063, unlike T, was de void of any specific binding to human plasma. In vivo, these compounds displayed antiandrogenic activity while being devoid of any agonistic effect. Thus, RU56187, given orally in castrated male animals, preven ted in a dose-dependent manner the effects of 3 mg/kg testosterone pro pionate (TP) on mouse renal ornithine decarboxylase (acute test) and o f 0.5 mg/kg TP on rat prostate weight (chronic test). In these two mod els, its ED(50) was 0.6 and 1 mg/kg, respectively. In the intact rat, when given alone, it inhibited dose-dependently the effect of endogeno us androgens on the seminal vesicles (ED(50) approximate to 1 mg/kg) a nd prostate (ED(50) approximate to 3 mg/kg) weights. These results sug gest that these new compounds may be useful as specific markers for th e androgen receptor as well as for the treatment of androgen-dependent diseases or disorders such as prostate cancer, acne, hirsutism and ma le pattern baldness.