Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors

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

Standard

Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors. / Rostrup, Frederik; Falk-petersen, Christina B.; Harpsøe, Kasper; Buchleithner, Stine; Conforti, Irene; Jung, Sascha; Gloriam, David E.; Schirmeister, Tanja; Wellendorph, Petrine; Frølund, Bente.

In: Journal of Medicinal Chemistry, Vol. 64, No. 8, 22.04.2021, p. 4730-4743.

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

Harvard

Rostrup, F, Falk-petersen, CB, Harpsøe, K, Buchleithner, S, Conforti, I, Jung, S, Gloriam, DE, Schirmeister, T, Wellendorph, P & Frølund, B 2021, 'Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors', Journal of Medicinal Chemistry, vol. 64, no. 8, pp. 4730-4743. https://doi.org/10.1021/acs.jmedchem.0c02163

APA

Rostrup, F., Falk-petersen, C. B., Harpsøe, K., Buchleithner, S., Conforti, I., Jung, S., Gloriam, D. E., Schirmeister, T., Wellendorph, P., & Frølund, B. (2021). Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors. Journal of Medicinal Chemistry, 64(8), 4730-4743. https://doi.org/10.1021/acs.jmedchem.0c02163

Vancouver

Rostrup F, Falk-petersen CB, Harpsøe K, Buchleithner S, Conforti I, Jung S et al. Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors. Journal of Medicinal Chemistry. 2021 Apr 22;64(8):4730-4743. https://doi.org/10.1021/acs.jmedchem.0c02163

Author

Rostrup, Frederik ; Falk-petersen, Christina B. ; Harpsøe, Kasper ; Buchleithner, Stine ; Conforti, Irene ; Jung, Sascha ; Gloriam, David E. ; Schirmeister, Tanja ; Wellendorph, Petrine ; Frølund, Bente. / Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors. In: Journal of Medicinal Chemistry. 2021 ; Vol. 64, No. 8. pp. 4730-4743.

Bibtex

@article{112b2ac4eb414bbc8014bc8337ed756d,
title = "Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors",
abstract = "Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABAARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30, 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6–16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABAARs in general.",
author = "Frederik Rostrup and Falk-petersen, {Christina B.} and Kasper Harps{\o}e and Stine Buchleithner and Irene Conforti and Sascha Jung and Gloriam, {David E.} and Tanja Schirmeister and Petrine Wellendorph and Bente Fr{\o}lund",
year = "2021",
month = apr,
day = "22",
doi = "10.1021/acs.jmedchem.0c02163",
language = "English",
volume = "64",
pages = "4730--4743",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

RIS

TY - JOUR

T1 - Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors

AU - Rostrup, Frederik

AU - Falk-petersen, Christina B.

AU - Harpsøe, Kasper

AU - Buchleithner, Stine

AU - Conforti, Irene

AU - Jung, Sascha

AU - Gloriam, David E.

AU - Schirmeister, Tanja

AU - Wellendorph, Petrine

AU - Frølund, Bente

PY - 2021/4/22

Y1 - 2021/4/22

N2 - Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABAARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30, 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6–16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABAARs in general.

AB - Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABAARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30, 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6–16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABAARs in general.

U2 - 10.1021/acs.jmedchem.0c02163

DO - 10.1021/acs.jmedchem.0c02163

M3 - Journal article

C2 - 33847501

VL - 64

SP - 4730

EP - 4743

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -

ID: 269662785