The mechanism by which the androgen receptor (AR) distinguishes between agonist and antagonist ligands is poorly understood. AR antagonists are currently used to treat prostate cancer. However, mutations commonly develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissueselective manner. To investigate why subtle structural changes to both the ligand and the receptor (i.e. mutations) result in drastic changes in activity, we studied structure-activity relationships for nonsteroidal AR ligands through crystallography and site-directed mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and R-3. These studies provide the first crystallographic evidence of the mechanism by which nonsteroidal ligands interact with the wild type AR. We have shown that changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for ligand accommodation within the AR binding pocket and that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and the ketone of hydroxyflutamide is present when bound to the T877A AR variant. Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in AR harboring the M895T point mutation. As a whole, these studies provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists. The androgen receptor (AR)3 is a ligand-inducible nuclear hormone receptor involved in regulation of prostate growth, muscle and bone mass, and spermatogenesis in males. Endogenous ligands for the AR include the steroid, testosterone, and its more potent metabolite, dihydrotestosterone (DHT). Agonist compounds for the AR provide therapeutic potential in the treatment of osteoporosis, cachexia, contraception, and androgen deficiency (1). Antagonist AR ligands are commonly used in the treatment of androgen-dependent prostate cancer. The clinically available nonsteroidal antiandrogens, flutamide and bicalutamide, are advantageous over steroidal drug treatments because of their oral bioavailability and lack of cross-reactivity with other steroid receptors. Mutations to the AR that cause resistance to antiandrogens by converting the compounds to agonists exist and represent a significant problem with currently prescribed prostate cancer drugs that target the AR (2-4). Different AR mutations cause agonism for hydroxyflutamide (HF, active form of flutamide) as compared with bicalutamide, suggesting that these ligands do not antagonize the AR by the same mechanism. Our recent report of the W741L-R-bicalutamide crystal structure (5) demonstrated that R-bicalutamide induces the same overall fold of the AR ligand binding domain (LBD) observed in steroidal androgen-bound AR LBD crystal structures when bound to a mutant AR associated with re...
Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.
The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies, including hormonal male contraception. The identification of an orally bioavailable SARM with the ability to mimic the central and peripheral androgenic and anabolic effects of testosterone would represent an important step toward the "male pill". We characterized the in vitro and in vivo pharmacologic activity of (S)-3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (C-6), a novel SARM developed in our laboratories. C-6 was identified as an androgen receptor (AR) agonist with high AR binding affinity (K i ϭ 4.9 nM). C-6 showed tissue-selective pharmacologic activity with higher anabolic activity than androgenic activity in male rats. The doses required to maintain the weight of the prostate, seminal vesicles, and levator ani muscle to half the size of the maximum effects (i.e., ED 50 ) were 0.78 Ϯ 0.06, 0.88 Ϯ 0.1, and 0.17 Ϯ 0.04 mg/day, respectively. As opposed to other SARMs, gonadotropin levels in C-6-treated groups were significantly lower than control values. C-6 also significantly decreased serum testosterone concentration in intact rats after 2 weeks of treatment. Marked suppression of spermatogenesis was observed after 10 weeks of treatment with C-6 in intact male rats. Pharmacokinetic studies of C-6 in male rats revealed that C-6 was well absorbed after oral administration (bioavailability 76%), with a long (6.3 h) half-life at a dose of 10 mg/kg. These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.Worldwide population growth and social awareness of reproductive health have stimulated a great deal of research in contraception. Although contraceptive pills have been available for women for decades, male contraception remains restricted to physical methods, such as condoms and vasectomy. However, many polls show that men would be more willing to be involved in family planning if appropriate contraceptive methods (i.e., a male contraceptive pill) were available (Anderson and Baird, 1997;Martin et al., 2000). Although the mechanism of spermatogenesis is not completely understood, inhibition of LH and FSH production is known to interrupt spermatogenesis. To date, the most practical method of male contraception is the hormonal approach. Potential regimens include androgen alone, androgen combined with progestins, and androgen combined with gonadotropin hormone-releasing hormone (GnRH) analogs (Amory and Bremner, 2001;Kamischke and Nieschlag, 2004). Among them, androgen-progestin combinations remain the most promising approach. Because androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, fat tissue distribution, and spermatogenesis (Matsumoto, 1994), an androgen supplement is a requi...
We examined the three-dimensional quantitative structure-activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r 2 and cross-validated q 2 relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r 2 of 0.954, demonstrating the excellent predictive ability of the model. These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs.
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