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.
Molecular Hybridization of Potent and Selective Î³-Hydroxybutyric Acid (GHB) Ligands: Design, Synthesis, Binding Studies, and Molecular Modeling of Novel 3-Hydroxycyclopent-1-enecarboxylic Acid (HOCPCA) and trans-Î³-Hydroxycrotonic Acid (T-HCA) Analogs / J. Krall, C.H. Jensen, F. Bavo, C.B. Falk-Petersen, A.S. Haugaard, S.B. Vogensen, Y. Tian, M. Nittegaard-Nielsen, S.B. Sigurdardã³ttir, J. Kehler, K.T. Kongstad, D.E. Gloriam, R.P. Clausen, K. Harpsã¸e, P. Wellendorph, B. Frølund. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 60:21(2017 Nov 09), pp. 9022-9039.
|Titolo:||Molecular Hybridization of Potent and Selective Î³-Hydroxybutyric Acid (GHB) Ligands: Design, Synthesis, Binding Studies, and Molecular Modeling of Novel 3-Hydroxycyclopent-1-enecarboxylic Acid (HOCPCA) and trans-Î³-Hydroxycrotonic Acid (T-HCA) Analogs|
|Parole Chiave:||Binding Sites; Carboxylic Acids; Crotonates; Cyclopentanes; Drug Design; Hydroxybutyrates; Ligands; Molecular Conformation; Structure-Activity Relationship; Models, Molecular; Molecular Medicine; Drug Discovery3003 Pharmaceutical Science|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||9-nov-2017|
|Data ahead of print / Data di stampa:||13-ott-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acs.jmedchem.7b01351|
|Appare nelle tipologie:||01 - Articolo su periodico|