ENANTIOSELECTIVE BINDING OF CASODEX TO THE ANDROGEN RECEPTOR

1. The biologic activity of androgens is mediated through the formatio n of a noncovalent androgen receptor (AR)-steroid complex. Casodex and other antiandrogens inhibit formation of this complex and thus negate the role of endogenous steroids in androgen-dependent growth of prost ate. 2. Casodex, is currently available as a racemic mixture. The goal of this investigation was to determine the in vitro AR binding affini ties of the individual isomers of Casodex. 3. The (R) or (S) isomers o f Casodex were synthesized according to the general synthetic scheme p roposed by Tucker et al. for (S)-Casodex, using (R) or (S)-proline: as the chiral matrix respectively. 4. ARs were isolated from rat ventral prostate tissue by homogenization and differential centrifugation, an d used as the receptor source. 5. AR binding studies Were conducted by incubation of the cytosol with 1 nM H-3-mibolerone (a synthetic andro gen) and increasing concentrations of each isomer (10(-12)-10(-5) M). Bound radioligand was quantitated by liquid scintillation counting. 6. K-i for (R)-Casodex (11.0+/-1.5 nM) was about 30 times lower than tha t of (S)Casodex (361+/-10 nM). K-i for the racemate was 20.2+/-2.0 nM. 7. This study demonstrated that (R)-Casodex has a higher binding affi nity than its stereoisomer and suggests that the antiandrogenic activi ty of racemic Casodex is almost completely due to the (R)-isomer.