Yin Donghua, He Yali, Perera Minoli A, Hong Seoung Soo, Marhefka Craig, Stourman Nina, Kirkovsky Leonid, Miller Duane D, Dalton James T
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Mol Pharmacol. 2003 Jan;63(1):211-23. doi: 10.1124/mol.63.1.211.
The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.
本研究的目的是检测源自已知抗雄激素药效基团的多个系列非甾体化合物的雄激素受体（AR）结合能力和体外功能活性，并研究这些非甾体化合物的构效关系（SARs）。通过使用从大鼠前列腺制备的胞质AR进行放射性配体竞争结合试验，评估了65种非甾体化合物的AR结合特性。利用共转染试验，通过配体调节培养的CV-1细胞中AR介导的转录激活的能力，测定高亲和力配体的AR激动剂和拮抗剂活性。具有不同结构特征的非甾体化合物对AR表现出广泛的结合亲和力。十种化合物，主要来自比卡鲁胺相关系列，显示出优于其衍生结构药效基团的结合亲和力。从结合数据中揭示了一些关于非甾体AR结合的构效关系，包括立体异构构象、空间效应和电子效应。高亲和力配体的功能活性范围从AR拮抗剂到完全激动剂。发现几个结构特征决定激动剂和拮抗剂活性。本研究中鉴定出的非甾体AR激动剂为雄激素治疗中选择性雄激素受体调节剂（SARMs）的进一步开发提供了一系列候选物。此外，这些研究揭示或证实了许多由非甾体分子控制AR结合和功能特性的重要构效关系，这将对未来SARMs的结构优化具有重要价值。
