Section 12
Chapter 11,942

Determination of the binding mode of thienopyrimidinedione antagonists to the human gonadotropin releasing hormone receptor using structure-activity relationships, site-directed mutagenesis, and homology modeling

Betz, S.F.; Lio, F.M.; Gao, Y.; Reinhart, G.J.; Guo, Z.; Mesleh, M.F.; Zhu, Y.-F.; Struthers, R.S.

Journal of Medicinal Chemistry 49(21): 6170-6176


ISSN/ISBN: 0022-2623
PMID: 17034124
DOI: 10.1021/jm060580w
Accession: 011941410

Download citation:  

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 the effect of several mutants on nonpeptide binding. Distinct interactions were observed in two separate regions: 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 the nonpeptides. Structure-activity relationships indicated urea substituents on the 6-(4-aminophenyl) group with 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)) and Y290((6.58)). These interaction sites facilitated the derivation of a model in which a representative member of the series was docked into GnRH-R. The model is consistent with known SAR and illuminates inconsistencies with previous hypotheses regarding how this series interacts with the receptor.

PDF emailed within 0-6 h: $19.90