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Molecular and Preclinical Pharmacology of Androgen Receptor Ligands

Jones, Amanda

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Pharmacy.
The androgen receptor (AR) is critical for the growth and development of secondary sexual organs, muscle, bone and other tissues, making it an excellent therapeutic target. Ubiquitous expression of AR impedes the ability of endogenous steroids to function tissue selectively. In addition to the lack of tissue selectivity, clinical use of testosterone is limited due to poor bioavailability and pharmacokinetic problems. Our lab, in the last decade, discovered and developed tissue selective AR modulators (SARMs) that spare androgenic effects in secondary sexual organs, but demonstrate potential to treat muscle wasting diseases. This work reveals the discovery of next generation SARMs to treat prostate cancer and mechanistically characterize a prospective SARM in muscle and central nervous system (CNS). Prostate cancer relies on the AR for its growth, making it the primary therapeutic target in this disease. However, prolonged inhibition, with commercially available AR antagonists, leads to the development of mutations in its ligand binding domain resulting in resistance. Utilizing the crystal structure of AR-wild-type and AR-W741L mutant, we synthesized a series of AR pan-antagonists (that inhibit both wild-type and mutant ARs). Structure activity relationship studies indicate that sulfonyl and amine linkages of the aryl propionamide pharmacophore are important for the antagonist activity. From a series of potent anabolic SARMs, S-23 was chosen to understand the mechanism for the prevention of glucocorticoid- and hypogonadism-induced myopathy. Muscle mass is maintained by a balance in protein synthesis and degradation pathways. Any alteration in this balance, in favor of the degradation pathway, results in muscle atrophy. Glucocorticoid- and castration-dependent dephosphorylation of Akt and up-regulation of ubiquitin ligases were inhibited by S-23. Interestingly, these results also discovered that hypogonadism inactivates the IGF-1/Akt pathway and glucocorticoids up-regulate ubiquitin ligases to induce muscle atrophy. In addition to full anabolic activity, S-23 functioned as an agonist in the CNS, at a dose above its muscle ED50, to suppress the hypothalamus-pituitary-gonadal axis. S-23 effectively and reversibly suppressed spermatogenesis in rats with concomitant beneficial effects on muscle, bone mineral density, and lean mass. Although the therapeutic window was narrow, coadministration with a progestin to rapidly suppress LH and FSH may broaden the therapeutic window and provide an oral agent for hormonal male contraception. Despite these changes in the HPG axis, S-23 enhanced female motivation in ovariectomized rats utilizing the partner preference paradigm. The effectiveness of SARMs in this study provides definitive proof of the importance of androgen receptor function to female sexual motivation. Collectively, these studies demonstrate the development of pan-AR antagonists and a novel mechanism for androgen function in muscle and CNS.
James T. Dalton, PhD (Advisor)
Thomas D. Schmittgen, PhD (Committee Member)
William L. Hayton, PhD (Committee Member)
Robert W. Brueggemeier, PhD (Committee Member)
153 p.

Recommended Citations

Citations

  • Jones, A. (2010). Molecular and Preclinical Pharmacology of Androgen Receptor Ligands [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1274895148

    APA Style (7th edition)

  • Jones, Amanda. Molecular and Preclinical Pharmacology of Androgen Receptor Ligands. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1274895148.

    MLA Style (8th edition)

  • Jones, Amanda. "Molecular and Preclinical Pharmacology of Androgen Receptor Ligands." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1274895148

    Chicago Manual of Style (17th edition)