Enantioselective binding of Casodex to the androgen receptor

Xenobiotica. 1996 Feb;26(2):117-22. doi: 10.3109/00498259609046693.


1. The biologic activity of androgens is mediated through the formation of a non-covalent 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 prostate. 2. Casodex is currently available as a racemic mixture. The goal of this investigation was to determine the in vitro AR binding affinities of the individual isomers of Casodex. 3. The (R) or (S) isomers of Casodex were synthesized according to the general synthetic scheme proposed 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, and used as the receptor source. 5. AR binding studies were conducted by incubation of the cytosol with 1 nM 3H-mibolerone (a synthetic androgen) and increasing concentrations of each isomer (10(-12) - 10(-5) M). Bound radioligand was quantitated by liquid scintillation counting. 6. Ki for (R)-Casodex (11.0 +/- 1.5 nM) was about 30 times lower than that of (S)-Casodex (364 +/- 10 nM). Ki for the racemate was 20.2 +/- 2.0 nM. 7. This study demonstrated that (R)-Casodex has a higher binding affinity than its stereoisomer and suggests that the antiandrogenic activity of racemic Casodex is almost completely due to the (R)-isomer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / metabolism*
  • Androgen Antagonists / pharmacokinetics
  • Anilides / metabolism*
  • Anilides / pharmacokinetics
  • Animals
  • Binding, Competitive / drug effects
  • Cytosol / metabolism
  • Kinetics
  • Male
  • Nandrolone / analogs & derivatives
  • Nandrolone / metabolism
  • Nitriles
  • Orchiectomy
  • Prostate / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / metabolism*
  • Stereoisomerism
  • Tosyl Compounds


  • Androgen Antagonists
  • Anilides
  • Nitriles
  • Receptors, Androgen
  • Tosyl Compounds
  • Nandrolone
  • mibolerone
  • bicalutamide