Key Structural Features of Nonsteroidal Ligands for Binding and Activation of the Androgen Receptor

TLDR

The study aimed to evaluate the AR binding and in vitro functional activity of diverse nonsteroidal compounds derived from antiandrogen pharmacophores and to elucidate their structure‑activity relationships. AR binding was measured for 65 compounds using a radioligand competitive assay with rat prostate cytosolic AR, and agonist/antagonist activities were assessed by AR‑mediated transcriptional activation in CV‑1 cells via a cotransfection assay. The compounds displayed a broad range of AR affinities, with ten bicalutamide‑related molecules exceeding the parent pharmacophore, and SAR analysis revealed stereochemistry, steric, and electronic effects that governed binding and determined whether ligands acted as antagonists or full agonists, providing promising candidates for selective androgen receptor modulator development.

Abstract

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.