Determination of the Binding Mode of Thienopyrimidinedione Antagonists to the Human Gonadotropin Releasing Hormone Receptor Using Structure-Activity Relationships, Site-Directed Mutagenesis, and Homol

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• 作者：Stephen F. Betz ; Francisco M. Lio ; Yinghong Gao ; Greg J. Reinhart ; Zhiqiang Guo ; Michael F. Mesleh ; Yun-Fei Zhu ; R. Scott Struthers
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：October 19, 2006
• 年：2006
• 卷：49
• 期：21
• 页码：6170 - 6176
• 全文大小：418K
• 年卷期：v.49,no.21(October 19, 2006)
• ISSN：1520-4804

文摘

We have investigated the specific interactions of a series thienopyrimidinediones with the gonadotropin-releasing hormone receptor (GnRH-R). Competitive radioligand binding assays were used to determine theeffect of several mutants on nonpeptide binding. Distinct interactions were observed in two separateregions: the N-terminal end of TM7 and the C-terminal end of TM6. The effects of mutants at D302^(7.32)and H306^(7.36) suggest that these residues are part of a hydrogen-bond network important for anchoring thenonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) groupwith a trans conformational preference bind with high affinity and are sensitive to D302^(7.32) mutations.Another interaction area was found between the N-benzyl-N-methylamino substituent and L300^(6.68) andY290^(6.58). These interaction sites facilitated the derivation of a model in which a representative member ofthe series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencieswith previous hypotheses regarding how this series interacts with the receptor.