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This version published online on October 23, 2009
Endocrinology, doi:10.1210/en.2009-0405
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Submitted on March 30, 2009
Accepted on September 21, 2009

A Novel Synthetic Androgen Receptor Ligand, S42, Works as a Selective Androgen Receptor Modulator and Possesses Metabolic Effects with Little Impact on the Prostate

Liu Min, Toshihiko Yanase, Tomoko Tanaka, WuQiang Fan, Masatoshi Nomura, Hisaya Kawate, Taijiro Okabe, Ryoichi Takayanagi, and Hajime Nawata*

Department of Medicine and Bioregulatory Science, Graduate School of Medical Science (L.M., T.Y., T.T., W.F., M.N., H.K., T.O., R.T.), Graduate School of Medical Science (H.N.), Department of Medical Biochemistry, Graduate School of Medical Science (L.M.), Kyushu University, Fukuoka 812-8582, Japan; and Department of Endocrinology and Diabetes Mellitus (T.Y., T.T.), School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan; Fukuoka Prefectural University (H.N.), Tagawa City, Fukuoka 825-8585, Japan

* To whom correspondence should be addressed. E-mail: nawata{at}intmed3.med.kyushu-u.ac.jp.

We identified a novel synthetic steroid, S42, as a promising candidate of selective androgen receptor (AR) modulator. Results of the whole-cell binding assay using COS-7 cells exogenously expressing various steroid receptors indicated that S42 specifically binds to AR and progesterone receptor. When orchiectomized Sprague Dawley rats were administered with S42 for 3 wk, the muscle weight of the levator ani was increased as markedly as that induced by 5{alpha}-dihydrotestosterone (DHT), but the weight of the prostate was not elevated at any doses in contrast to DHT. The plasma concentrations of gonadotropin and adiponectin, those down-regulated by DHT, were unaffected by S42. In addition, although the plasma triglyceride level was unaffected by DHT, it was significantly reduced by S42. This effect of S42 was associated with suppression of the SRBP-1c-mediated lipogenic and insulin-desensitizing pathway in the liver and visceral fat. Taken together, S42 works as an AR agonist in muscle and as an AR antagonist in the prostate, pituitary gland, and liver, accompanying beneficial potentials on lipid metabolism.






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