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Vol. 63, Issue 1, 211-223, January 2003
Division of Pharmaceutics and Pharmaceutical Chemistry, College of
Pharmacy, The Ohio State University, Columbus, Ohio (D.Y., M.A.P.,
J.T.D.); and Department of Pharmaceutical Sciences, College of
Pharmacy, University of Tennessee, Memphis, Tennessee (Y.H., S.S.H.,
C.M., N.S., L.K., D.D.M.)
The purposes of the present studies were to examine the androgen
receptor (AR) binding ability and in vitro functional activity of
multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a
radioligand competitive binding assay with the use of cytosolic AR
prepared from rat prostates. The AR agonist and antagonist activities
of high-affinity ligands were determined by the ability of the ligand
to regulate AR-mediated transcriptional activation in cultured CV-1
cells, using a cotransfection assay. Nonsteroidal compounds with
diverse structural features demonstrated a wide range of binding
affinity for the AR. Ten compounds, mainly from the
bicalutamide-related series, showed a binding affinity superior to the
structural pharmacophore from which they were derived. Several SARs
regarding nonsteroidal AR binding were revealed from the binding data,
including stereoisomeric conformation, steric effect, and electronic
effect. The functional activity of high-affinity ligands ranged from
antagonist to full agonist for the AR. Several structural features were
found to be determinative of agonist and antagonist activities. The
nonsteroidal AR agonists identified from the present studies provided a
pool of candidates for further development of selective androgen
receptor modulators (SARMs) for androgen therapy. Also, these studies
uncovered or confirmed numerous important SARs governing AR binding and
functional properties by nonsteroidal molecules, which would be
valuable in the future structural optimization of SARMs.
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