PT  - JOURNAL ARTICLE
AU  - Yin, Donghua
AU  - He, Yali
AU  - Perera, Minoli A.
AU  - Hong, Seoung Soo
AU  - Marhefka, Craig
AU  - Stourman, Nina
AU  - Kirkovsky, Leonid
AU  - Miller, Duane D.
AU  - Dalton, James T.
TI  - Key Structural Features of Nonsteroidal Ligands for Binding and Activation of the Androgen Receptor
AID  - 10.1124/mol.63.1.211
DP  - 2003 Jan 01
TA  - Molecular Pharmacology
PG  - 211--223
VI  - 63
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/63/1/211.short
4100  - http://molpharm.aspetjournals.org/content/63/1/211.full
SO  - Mol Pharmacol2003 Jan 01; 63
AB  - 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.