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 trans-γ-Hydroxycrotonic Acid (T-HCA) Analogs

  • J Med Chem. 2017 Nov 9;60(21):9022-9039. doi: 10.1021/acs.jmedchem.7b01351.
Jacob Krall  1 ,  Claus Hatt Jensen  1 ,  Francesco Bavo  1  2 ,  Christina Birkedahl Falk-Petersen  1 ,  Anne Stæhr Haugaard  1 ,  Stine Byskov Vogensen  1 ,  Yongsong Tian  1 ,  Mia Nittegaard-Nielsen  1 ,  Sara Björk Sigurdardóttir  1 ,  Jan Kehler  3 ,  Kenneth Thermann Kongstad  1 ,  David E Gloriam  1 ,  Rasmus Prætorius Clausen  1 ,  Kasper Harpsøe  1 ,  Petrine Wellendorph  1 ,  Bente Frølund  1
Affiliations
  • 1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2100 Copenhagen, Denmark.
  • 2. Department of Pharmaceutical Sciences, University of Milan , 20133 Milan, Italy.
  • 3. Discovery Chemistry, H. Lundbeck A/S , Ottiliavej 9, DK-2500 Valby, Denmark.
PMID: 29028338 DOI: 10.1021/acs.jmedchem.7b01351
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 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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