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

Jacob Krall; Claus Hatt Jensen; Francesco Bavo; Christina Birkedahl Falk-Petersen; Anne Stæhr Haugaard; Stine Byskov Vogensen; Yongsong Tian; Mia Nittegaard-Nielsen; Sara Björk Sigurdardóttir; Jan Kehler; Kenneth Thermann Kongstad; David E. Gloriam; Rasmus Prætorius Clausen; Kasper Harpsøe; Petrine Wellendorph; Bente Frølund

doi:10.1021/acs.jmedchem.7b01351

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

Jacob Krall, Claus Hatt Jensen, Francesco Bavo, Christina Birkedahl Falk-Petersen, Anne Stæhr Haugaard, Stine Byskov Vogensen, Yongsong Tian, Mia Nittegaard-Nielsen, Sara Björk Sigurdardóttir, Jan Kehler, Kenneth Thermann Kongstad, David E. Gloriam, Rasmus Prætorius Clausen, Kasper Harpsøe, Petrine Wellendorph, Bente Frølund

8 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	21
Pages (from-to)	9022-9039
Number of pages	18
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01351
Publication status	Published - 9 Nov 2017

Keywords

Former Faculty of Pharmaceutical Sciences

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Krall, J., Jensen, C. H., Bavo, F., Falk-Petersen, C. B., Haugaard, A. S., Vogensen, S. B., Tian, Y., Nittegaard-Nielsen, M., Sigurdardóttir, S. B., Kehler, J., Kongstad, K. T., Gloriam, D. E., Clausen, R. P., Harpsøe, K., Wellendorph, P., & Frølund, B. (2017). 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. Journal of Medicinal Chemistry, 60(21), 9022-9039. https://doi.org/10.1021/acs.jmedchem.7b01351

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. / Krall, Jacob; Jensen, Claus Hatt; Bavo, Francesco et al.
In: Journal of Medicinal Chemistry, Vol. 60, No. 21, 09.11.2017, p. 9022-9039.

Research output: Contribution to journal › Journal article › Research › peer-review

Krall, J, Jensen, CH, Bavo, F, Falk-Petersen, CB, Haugaard, AS, Vogensen, SB, Tian, Y, Nittegaard-Nielsen, M, Sigurdardóttir, SB, Kehler, J, Kongstad, KT , Gloriam, DE , Clausen, RP , Harpsøe, K , Wellendorph, P & Frølund, B 2017, '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', Journal of Medicinal Chemistry, vol. 60, no. 21, pp. 9022-9039. https://doi.org/10.1021/acs.jmedchem.7b01351

Krall J, Jensen CH, Bavo F, Falk-Petersen CB, Haugaard AS, Vogensen SB et al. 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. Journal of Medicinal Chemistry. 2017 Nov 9;60(21):9022-9039. doi: 10.1021/acs.jmedchem.7b01351

Krall, Jacob ; Jensen, Claus Hatt ; Bavo, Francesco et al. / 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. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 21. pp. 9022-9039.

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title = "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",

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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T1 - 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

AU - Krall, Jacob

AU - Jensen, Claus Hatt

AU - Bavo, Francesco

AU - Falk-Petersen, Christina Birkedahl

AU - Haugaard, Anne Stæhr

AU - Vogensen, Stine Byskov

AU - Tian, Yongsong

AU - Nittegaard-Nielsen, Mia

AU - Sigurdardóttir, Sara Björk

AU - Kehler, Jan

AU - Kongstad, Kenneth Thermann

AU - Gloriam, David E.

AU - Clausen, Rasmus Prætorius

AU - Harpsøe, Kasper

AU - Wellendorph, Petrine

AU - Frølund, Bente

PY - 2017/11/9

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N2 - 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.

AB - 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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