4-hydroxy-2-butenoic-acid and 3-hydroxycyclopent-1-enecarboxylic-acid

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 K

Topics: Binding Sites; Carboxylic Acids; Crotonates; Cyclopentanes; Drug Design; Hydroxybutyrates; Ligands; Models, Molecular; Molecular Conformation; Structure-Activity Relationship