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

Research output: Contribution to journalJournal articlepeer-review

Standard

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

In: Journal of Medicinal Chemistry, Vol. 60, No. 21, 2017, p. 9022-9039.

Research output: Contribution to journalJournal articlepeer-review

Harvard

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

APA

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

Vancouver

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;60(21):9022-9039. https://doi.org/10.1021/acs.jmedchem.7b01351

Author

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

Bibtex

@article{240820da2b1b4180b7549cf8abeb34c5,
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.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Jacob Krall and Jensen, {Claus Hatt} and Francesco Bavo and Falk-Petersen, {Christina Birkedahl} and Haugaard, {Anne St{\ae}hr} and Vogensen, {Stine Byskov} and Yongsong Tian and Mia Nittegaard-Nielsen and Sigurdard{\'o}ttir, {Sara Bj{\"o}rk} and Jan Kehler and Kongstad, {Kenneth Thermann} and Gloriam, {David E.} and Clausen, {Rasmus Pr{\ae}torius} and Kasper Harps{\o}e and Petrine Wellendorph and Bente Fr{\o}lund",
year = "2017",
doi = "10.1021/acs.jmedchem.7b01351",
language = "English",
volume = "60",
pages = "9022--9039",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

RIS

TY - JOUR

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

Y1 - 2017

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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/acs.jmedchem.7b01351

DO - 10.1021/acs.jmedchem.7b01351

M3 - Journal article

C2 - 29028338

VL - 60

SP - 9022

EP - 9039

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -

ID: 185276297