Forskning ved Københavns Universitet - Københavns Universitet


Molecular hybridization of potent and selective γ-Hydroxybutyric Acid (GHB) ligands; Design, synthesis, binding studies, and molecular modelling of novel 3-hydroxycyclopent-1-enecarboxylic Acid (HOCPCA) and trans-γ-hydroxycrotonic acid (T-HCA) Analogs

Publikation: Forskning - peer reviewTidsskriftartikel

Jacob Krall, Claus Hatt Jensen, Francesco Bavo, Christina Birkedal Falk-Petersen, Anne Stahr Haugaard, Stine Byskov Vogensen, Yongsong Tian, Mia Nittegaard-Nielsen, Sara Björk Sigurdardóttir, Jan Kehler, Kenneth Thermann Kongstad, David E Gloriam, Rasmus Prætorius Clausen, Kasper Harpsøe, Petrine Wellendorph, Bente Frølund

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 3-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.

TidsskriftJournal of medicinal chemistry
StatusE-pub ahead of print - 13 okt. 2017

ID: 184712129