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

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 highaffinity 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.

Antiandrogenic properties of parabens and other phenolic containing small molecules in personal care products

“…Recent reports of several non-steroidal compounds that have the ability to bind and activate the androgen receptor (AR) are of particular concern because many of these xenobiotics are ubiquitous in daily life and some are present as high production volume (HPV) compounds that are manufactured or imported into the United States in millions of pounds per year. The presence of these compounds in the environment has stimulated new interest in the identification of environmental contaminants that may act as selective AR modulators (SARMs) (Yin et al, 2003;Bohl et al, 2004;Chen et al, 2005).…”

Pharmacology, Pharmacokinetics, and Metabolism of Acetothiolutamide, a Novel Nonsteroidal Agonist for the Androgen Receptor

“…The ability of acetothiolutamide to influence AR-mediated transcriptional activation was examined using a cotransfection system, as described previously (Yin et al, 2003). Briefly, monkey kidney CV-1 cells (American Type Culture Collection, Manassas, VA) were seeded into 12-well tissue culture plates at a density of 2 ϫ 10 5 cells/well and transiently transfected with 50 ng of a human AR expression construct (pCMVhAR; generously provided by Dr. Donald J. Tindall, Mayo Clinic and Mayo Foundation, Rochester, MN), 1 g of an androgen-dependent luciferase reporter construct (pMMTVLuc; generously provided by Dr. Ronald Evans, The Salk Institute, San Diego, CA), and 1 g of a ␤-galactosidase expression construct (pSV-␤-galactosidase; Promega, Madison, WI) for constitutive expression of ␤-galactosidase using LipofectAMINE.…”

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

“…Extensive SAR studies (57,(62)(63)(64) show that both the ether linkage and B-ring para-position substituents are critical for the agonist activity of these bicalutamide derivatives (62). Based on available crystal structures, compounds with the ether linkage adopt a more compact conformation than bicalutamide due to the establishment of an intramolecular H bond (65), allowing the B-ring to avoid steric conflict with the side chain of W741 in the wild type AR (as is observed with bicalutamide) (66) and potentially explaining the agonist activity observed in compounds incorporating ether or thio-ether linkages.…”