T-HCA

Abstract: 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 f...

Abstract: Trans 4-hydroxycrotonic acid (T-HCA) has been identified in central nervous system of mammalians as a naturally occuring substance, which may compete with 4-hydroxybutyric acid (GHB) for specific biological targets, such as high affinity binding sites, uptake systems and metabolism enzymes. T-HCA has been tritiated at the 2,3 positions, using a multi-step synthesis and a one-pot reaction for the three last critical steps. Thus, T-HCA-[2,3-3H] was obtained with a specific radioactivity of 45 Ci/mmole (1.66 TBq/mmole) and a radiochemical purity of 97%.