11 research outputs found
Selective mGAT2 (BGT-1) GABA Uptake Inhibitor:Design, synthesis and pharmacological characterization
Molecular Hybridization of Potent and Selective γ‑Hydroxybutyric Acid (GHB) Ligands: Design, Synthesis, Binding Studies, and Molecular Modeling of Novel 3‑Hydroxycyclopent-1-enecarboxylic Acid (HOCPCA) and <i>trans</i>-γ-Hydroxycrotonic Acid (T-HCA) Analogs
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 <i>trans</i>-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 <i>K</i><sub>i</sub>) 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