Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor

Donghua Yin, Yali He, Minoli A. Perera, Seoung Soo Hong, Craig Marhefka, Nina Stourman, Leonid Kirkovsky, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)211-223
Number of pages13
JournalMolecular Pharmacology
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2003

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Androgen Receptors
Ligands
Androgens
Structure-Activity Relationship
Androgen Receptor Antagonists
Androgen Antagonists
Competitive Binding
Transcriptional Activation
Prostate

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Yin, D., He, Y., Perera, M. A., Hong, S. S., Marhefka, C., Stourman, N., ... Dalton, J. T. (2003). Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. Molecular Pharmacology, 63(1), 211-223. https://doi.org/10.1124/mol.63.1.211

Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. / Yin, Donghua; He, Yali; Perera, Minoli A.; Hong, Seoung Soo; Marhefka, Craig; Stourman, Nina; Kirkovsky, Leonid; Miller, Duane; Dalton, James T.

In: Molecular Pharmacology, Vol. 63, No. 1, 01.01.2003, p. 211-223.

Research output: Contribution to journalArticle

Yin, D, He, Y, Perera, MA, Hong, SS, Marhefka, C, Stourman, N, Kirkovsky, L, Miller, D & Dalton, JT 2003, 'Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor', Molecular Pharmacology, vol. 63, no. 1, pp. 211-223. https://doi.org/10.1124/mol.63.1.211
Yin, Donghua ; He, Yali ; Perera, Minoli A. ; Hong, Seoung Soo ; Marhefka, Craig ; Stourman, Nina ; Kirkovsky, Leonid ; Miller, Duane ; Dalton, James T. / Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. In: Molecular Pharmacology. 2003 ; Vol. 63, No. 1. pp. 211-223.
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