Journal of Medicinal Chemistry p. 9022 - 9039 (2017)
Update date:2022-08-15
Topics:
Krall, Jacob
Jensen, Claus Hatt
Bavo, Francesco
Falk-Petersen, Christina Birkedahl
Haugaard, Anne St?hr
Vogensen, Stine Byskov
Tian, Yongsong
Nittegaard-Nielsen, Mia
Sigurdardóttir, Sara Bj?rk
Kehler, Jan
Kongstad, Kenneth Thermann
Gloriam, David E.
Clausen, Rasmus Pr?torius
Harps?e, Kasper
Wellendorph, Petrine
Fr?lund, Bente
γ-Hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog trans-4-hydroxycrotonic acid (T-HCA). In general, all structural modifications performed on HOCPCA led to reduced affinity. In contrast, introduction of diaromatic substituents into the 4-position of T-HCA led to high-affinity analogs (medium nanomolar Ki) for the GHB high-affinity binding sites as the most high-affinity analogs reported to date. The SAR data formed the basis for a three-dimensional pharmacophore model for GHB ligands, which identified molecular features important for high-affinity binding, with high predictive validity. These findings will be valuable in the further processes of both target characterization and ligand identification for the high-affinity GHB binding sites.
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