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Department of Biochemistry and Molecular Biology Johns Hopkins Bloomberg School of Public Health Baltimore, Maryland 21205
Address all correspondence and requests for reprints to: Terry R. Brown, Ph.D., Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205. E-mail: tbrown{at}jhsph.edu.
Androgens play an essential role in differentiation and growth of the male reproductive tract, pubertal maturation and development of secondary male sex characteristics, initiation and regulation of spermatogenesis, and male sexual behavior (1). Steroidal androgens increase muscle mass, bone mass, and strength; stimulate male pattern baldness; and alter serum lipid profiles and fat distribution (2). Testosterone (T), synthesized and secreted by the testes, and its more potent 5
-reduced metabolite, dihydrotestosterone (DHT), are the principal biologically active endogenous androgens. T and DHT exert tissue-specific biological effects. For example, T functions to stimulate muscle mass, sexual development, and spermatogenesis, whereas DHT plays critical roles in facial and body hair growth, acne, and prostatic enlargement. The actions of both T and DHT are mediated by the intracellular androgen receptor (AR), a member of the nuclear receptor superfamily of ligand-activated transcription factors (3, 4). Upon binding of T or DHT, AR undergoes a conformational change, binds to specific DNA sequences termed androgen response elements, forms complexes with nuclear coregulatory factors, and modulates the transcription of target genes. For decades, AR has been a target for drug development focused upon the treatment of pathological conditions arising from abnormal androgen levels or altered target tissue responsiveness, the improvement of physical performance, and the regulation of male fertility.
The primary focus for drug design has been the synthesis of chemicals to regulate the transcriptional activity of AR based upon the structural, steroidal or nonsteroidal, and functional androgenic, antiandrogenic, or anabolic properties of ligands. Steroidal androgens, represented by various chemical derivatives of T, have been used clinically to treat a variety of male and female disorders resulting from androgen deficiency (5, 6). The principal clinical indication for androgens is as replacement therapy in hypogonadal men. Androgens have also been used clinically for the treatment of delayed puberty in boys, anemia, primary osteoporosis, hereditary angioneurotic edema, endometriosis, and muscle diseases and wasting. More recently, androgens have been used as hormone replacement therapy in aging men and for regulation of male fertility. The use and abuse of androgens as anabolic agents to enhance physical performance and endurance has been highlighted recently among world-class athletes participating in the Olympic games, as well as among adolescents seeking athletic achievement. Antiandrogens are used to counteract the undesirable actions of excessive androgens to treat acne, hirsutism, and male pattern baldness and to prevent androgen stimulation of prostatic hyperplasia and carcinoma. Nonsteroidal antiandrogens (Fig. 1
), such as flutamide (Eulexin; Schering, Kenilworth, NJ), nilutamide (Anandron; Aventis, Kansas City, MO), and bicalutamide (Casodex; AstraZeneca, Wilmington, DE), are referred to as pure antiandrogens because they bind exclusively to AR and thus are devoid of antigonadotropic, antiestrogenic, and progestational effects (7). These agents have advantages over steroidal antiandrogens such as megesterol acetate or cyproterone acetate in terms of specificity, selectivity, and pharmacokinetic properties.
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The current report by Gao et al. (9) describes the tissue selectivity in intact male rats of two SARMs, designated S1 and S4, that behave as partial agonists in androgen-responsive tissues, such as prostate and seminal vesicles, but full agonists in anabolic tissues such as the levator ani muscle (12). Both S1 and S4 bind with high affinity to AR, with dissociation constant of the ligand inhibitor-receptor complex (Ki) values of 6.1 and 4.0 nM, respectively; which is similar to T, much higher than hydroxyflutamide (Ki = 25 nM), but lower than DHT (Ki = 0.2 nM). In immature castrated rats, S1 and S4 exhibited full AR agonist activity in levator ani muscle but only partial agonist activity in prostate and seminal vesicles. The relative rates of efficacy of S1 and S4 in prostate were 12 and 29%, respectively, compared with T propionate. As reported by Gao et al. (9) for intact male rats, S1 selectively decreased prostate weight with efficacy similar to that of the 5-reductase inhibitor finasteride without affecting the levator ani muscle or altering the plasma levels of T, LH, or FSH. By contrast, hydroxyflutamide decreased both the prostate and levator ani muscle weights without selectivity and increased plasma hormone levels in a dose-dependent fashion. Neither S1 nor S4 affected 5-reductase type I or II isozyme activities. These results show that S1 and S4 act as partial AR agonists with tissue-selective activity that suppresses androgen-dependent prostate growth without influencing the anabolic effects of T on weight of the levator ani muscle. Moreover, the maintenance of normal serum T levels and lack of effect of S1 and S4 on pituitary gonadotropin secretion further exemplify the tissue selectivity of their action.
The derivation of S1 and S4 is based on earlier studies by this group of investigators that focused upon key structural elements previously determined to be important for AR binding of nonsteroidal ligands, such as bicalutamide and hydroxyflutamide (20, 21). In their evaluation of structure-activity relationships for nonsteroidal ligands, AR binding affinity of bicalutamide derivatives was enhanced in the R-isomers defined by the sulfur linkage to the meta-carbon in the aromatic B-ring, by an electrophilic para-substituent in the aromatic B-ring, by a nitro group in the para-position of the A-ring, and by a trifluoromethyl group linked to the chiral carbon (11). They discovered, however, that hepatic oxidation of the sulfur linkage led to rapid in vivo inactivation and reduced efficacy of several bicalutamide derivatives (22). To block oxidation, the thio linkage was modified to an ether linkage, creating the S-isomers, and a fluoride (S1), propionate (S3), or acetamido group (S4) was placed in the para-position of the B-ring (Fig. 2). This group of compounds demonstrated high in vitro AR binding affinity and efficacy in assays of AR-mediated reporter gene activity, but only S1 and S4 exerted in vivo androgenicity (increased prostate and seminal vesicle weights) and anabolic activity (increased levator ani muscle weight) in castrated immature rats (12). In the context of these findings, it is important to point out that in vitro binding affinity cannot distinguish agonist or antagonist activity. Moreover, observation of in vitro agonist activity of a compound in transfection assays does not always predict in vivo efficacy that is additionally influenced by route of administration, disposition, and metabolism.
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-helices. In the crystal structure, relatively few amino acid residues were found to interact directly with the steroidal agonists, DHT and methyltrienolone (R1881) (25, 26). Most of these residues are hydrophobic in nature and interact with hydrophobic moieties in the ligand, whereas fewer residues are hydrophilic and may form hydrogen bonds with polar atoms in the ligand. In the case of nonsteroidal ligands, AR binding is likely to be influenced by stereoisomeric conformation and steric and electronic effects. It remains to be determined whether the same amino acids in the ligand binding pocket interact with both steroidal and nonsteroidal ligands. As evidenced by structure-function studies of nonsteroidal ligands, minor differences in ligand structure can lead to either agonist or antagonist activity (11). The AR can use different transactivation domains, AF-1 and AF-5 in the amino-terminal domain and AF-2 in the carboxy-terminal domain (27, 28, 29, 30). The AF-2 function is strongly dependent upon interaction with nuclear receptor coactivators, whereas strong agonist, but not antagonist, binding induces ligand-dependent interaction internally between the AF-2 and AF-1 domains (31, 32, 33). When steroid agonists bind to AR, helix 12 containing the AF-2 region in the ligand binding domain closes over the binding pocket revealing an interface for coactivator interaction. Conversely, binding of antagonists maintains helix 12 in an open conformation directed away from the binding pocket. Therefore, tissue selectivity of nonsteroidal androgen action may depend upon ligand-induced AR conformation and recruitment of a tissue-specific repertoire of coregulatory factors that function as coactivators or corepressors. In summary, the novel features of designer androgens may find application in numerous medical situations. The potent androgenic/anabolic effects on muscle, bone, and mental function may improve the quality of life for those with chronic diseases or for aging men if the potential adverse effects on the cardiovascular system and the prostate can be divorced. Although the factors that determine tissue selectivity of androgen action remain to be explored, the current report by Gao et al. (9) confirms the critical nature that ligand structure plays in regulating AR function in different tissues. The flexibility in design of nonsteroidal AR ligands provides the opportunity to exploit the beneficial effects of androgens while ameliorating their undesirable effects.
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Footnotes |
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Received September 10, 2004.
Accepted for publication September 15, 2004.
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-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia. Endocrinology 145:5420–5428This article has been cited by other articles:
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  T. Kuuranne, A. Leinonen, W. Schanzer, M. Kamber, R. Kostiainen, and M. Thevis Aryl-Propionamide-Derived Selective Androgen Receptor Modulators: Liquid Chromatography-Tandem Mass Spectrometry Characterization of the in Vitro Synthesized Metabolites for Doping Control Purposes Drug Metab. Dispos., March 1, 2008; 36(3): 571 - 581. [Abstract] [Full Text] [PDF]
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 T.-V. V. Nguyen, M. Yao, and C. J. Pike Flutamide and Cyproterone Acetate Exert Agonist Effects: Induction of Androgen Receptor-Dependent Neuroprotection Endocrinology, June 1, 2007; 148(6): 2936 - 2943. [Abstract] [Full Text] [PDF]
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D. Wu, Z. Wu, J. Yang, V. A. Nair, D. D. Miller, and J. T. Dalton PHARMACOKINETICS AND METABOLISM OF A SELECTIVE ANDROGEN RECEPTOR MODULATOR IN RATS: IMPLICATION OF MOLECULAR PROPERTIES AND INTENSIVE METABOLIC PROFILE TO INVESTIGATE IDEAL PHARMACOKINETIC CHARACTERISTICS OF A PROPANAMIDE IN PRECLINICAL STUDY Drug Metab. Dispos., March 1, 2006; 34(3): 483 - 494. [Abstract] [Full Text] [PDF]
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