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Chemistry and structural biology of androgen receptor.

Androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily,1 which is composed of over 100 members and continues to grow. Among this large family of proteins, only five vertebrate steroid receptors—estrogen, progesterone, androgen, glucocorticoid, and mineralocorticoid receptors—are known. Two subtypes of estrogen receptor have been identified, estrogen receptor α and estrogen receptor β.2 Like other steroid receptors, AR is a soluble protein that functions as an intracellular transcriptional factor. AR function is regulated by the binding of androgens, which initiates sequential conformational changes of the receptor that affect receptor–protein interactions and receptor–DNA interactions. 
 
AR-regulated gene expression is responsible for male sexual differentiation and male pubertal changes. AR ligands are widely used in a variety of clinical applications (i.e., agonists are employed for hypogonadism, while antagonists are used for prostate cancer therapy). Fang et al.3 recently summarized a large number of chemicals that bind to the AR. The current review focuses on well-characterized AR ligands that bind to the AR with high affinity and integrates discussion regarding the biology, metabolism, and structure-activity relationships for therapeutic and emerging classes of AR ligands. The known AR ligands can be classified as steroidal or nonsteroidal based on their structure or as agonist or antagonist based on their ability to activate or inhibit transcription of AR target genes. Synthetic AR ligands were first developed by modifying the steroidal structure of endogenous androgens. The structure–activity relationship of these steroidal AR ligands is well documented4-6 and will only be briefly summarized in this review. However, low oral bio-availability, poor pharmacokinetic properties, and side effects have limited the use of many steroidal AR ligands. Until recently, it was considered impossible to separate the androgenic and anabolic effects of AR ligands due to their reliance on a single AR. However, newly discovered nonsteroidal AR ligands may provide a new strategy to achieve tissue selectivity, as is possible with estrogen receptor ligands. Novel nonsteroidal pharmacophores are summarized in this review with discussion of the emerging structure–activity relationships and examples of their tissue selectivity included.7 
 
1.1. Physiologic Roles and Clinical Application of Androgens 
AR is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest expression level observed in the prostate, adrenal gland, and epididymis as determined by real-time polymerase chain reaction (PCR).8 AR can be activated by the binding of endogenous androgens, including testosterone and 5α-dihydrotestosterone (5α-DHT). Physiologically, functional AR is responsible for male sexual differentiation in utero and for male pubertal changes. In adult males, androgen is mainly responsible for maintaining libido, spermato-genesis, muscle mass and strength, bone mineral density, and erythropoisis.7,9 The actions of androgen in the reproductive tissues, including prostate, seminal vesicle, testis, and accessory structures, are known as the androgenic effects, while the nitrogen-retaining effects of androgen in muscle and bone are known as the anabolic effects. 
 
Numerous and varied site mutations in AR have been identified (The Androgen Receptor Gene Mutations Database World Wide Web Server, http://www.androgendb.mcgill.ca/). The majority of these mutations are associated with diseases, like Androgen Insensitivity Syndrome and prostate cancer. The androgen withdrawal syndrome observed in prostate cancer therapy also appeared to be related to certain AR mutations, such as T877A and W741C mutations, which convert some AR antagonists into agonists (see more discussion in section 3.1.1). Besides the site mutations documented, AR gene polymorphism has also been identified, particularly, the poly-Q (CAG)n at exon I. The polymorphic (CAG)10–35 triplet repeat sequence, starting from codon 58, codes for polyglutamine. The length of the repeat is inversely correlated with the transactivation activity of AR. The correlation between the length of the CAG repeat and disease stage was recently reviewed by Oettel.10 
 
Classically, testosterone is used to treat male hypogonadism, Klinefelter's syndrome, anemia secondary to chronic renal failure, aplastic anemia, protein wasting diseases associated with cancer, burns, traumas,acquiredimmunodeficiencysyndrome(AIDS), etc., short stature, breast cancer (as an anti-estrogen), and hereditary angioedema.7 Recently, hormone replacement therapy in aging males has also been proposed to improve body composition, bone and cartilage metabolism, and certain domains of brain function and even decrease cardiovascular risk.10