Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors

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

Standard

Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors. / Yakoub, Kirsten; Jung, Sascha; Sattler, Christian; Damerow, Helen; Weber, Judith; Kretzschmann, Annika; Cankaya, Aylin S; Piel, Markus; Rösch, Frank; Haugaard, Anne S; Frølund, Bente; Schirmeister, Tanja; Lüddens, Hartmut.

In: Journal of Medicinal Chemistry, Vol. 61, No. 5, 08.03.2018, p. 1951-1968.

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

Harvard

Yakoub, K, Jung, S, Sattler, C, Damerow, H, Weber, J, Kretzschmann, A, Cankaya, AS, Piel, M, Rösch, F, Haugaard, AS, Frølund, B, Schirmeister, T & Lüddens, H 2018, 'Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors', Journal of Medicinal Chemistry, vol. 61, no. 5, pp. 1951-1968. https://doi.org/10.1021/acs.jmedchem.7b01484

APA

Yakoub, K., Jung, S., Sattler, C., Damerow, H., Weber, J., Kretzschmann, A., Cankaya, A. S., Piel, M., Rösch, F., Haugaard, A. S., Frølund, B., Schirmeister, T., & Lüddens, H. (2018). Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors. Journal of Medicinal Chemistry, 61(5), 1951-1968. https://doi.org/10.1021/acs.jmedchem.7b01484

Vancouver

Yakoub K, Jung S, Sattler C, Damerow H, Weber J, Kretzschmann A et al. Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors. Journal of Medicinal Chemistry. 2018 Mar 8;61(5):1951-1968. https://doi.org/10.1021/acs.jmedchem.7b01484

Author

Yakoub, Kirsten ; Jung, Sascha ; Sattler, Christian ; Damerow, Helen ; Weber, Judith ; Kretzschmann, Annika ; Cankaya, Aylin S ; Piel, Markus ; Rösch, Frank ; Haugaard, Anne S ; Frølund, Bente ; Schirmeister, Tanja ; Lüddens, Hartmut. / Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 5. pp. 1951-1968.

Bibtex

@article{dfb19fae1e2f4e598e8ceba77bbbb587,
title = "Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors",
abstract = "δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.",
keywords = "GABA-A Receptor Antagonists/chemistry, Humans, Imidazoles/chemistry, Inhibitory Concentration 50, Protein Subunits/metabolism, Pyridines/chemistry, Receptors, GABA-A/metabolism, Structure-Activity Relationship",
author = "Kirsten Yakoub and Sascha Jung and Christian Sattler and Helen Damerow and Judith Weber and Annika Kretzschmann and Cankaya, {Aylin S} and Markus Piel and Frank R{\"o}sch and Haugaard, {Anne S} and Bente Fr{\o}lund and Tanja Schirmeister and Hartmut L{\"u}ddens",
year = "2018",
month = mar,
day = "8",
doi = "10.1021/acs.jmedchem.7b01484",
language = "English",
volume = "61",
pages = "1951--1968",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

T1 - Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors

AU - Yakoub, Kirsten

AU - Jung, Sascha

AU - Sattler, Christian

AU - Damerow, Helen

AU - Weber, Judith

AU - Kretzschmann, Annika

AU - Cankaya, Aylin S

AU - Piel, Markus

AU - Rösch, Frank

AU - Haugaard, Anne S

AU - Frølund, Bente

AU - Schirmeister, Tanja

AU - Lüddens, Hartmut

PY - 2018/3/8

Y1 - 2018/3/8

N2 - δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.

AB - δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.

KW - GABA-A Receptor Antagonists/chemistry

KW - Humans

KW - Imidazoles/chemistry

KW - Inhibitory Concentration 50

KW - Protein Subunits/metabolism

KW - Pyridines/chemistry

KW - Receptors, GABA-A/metabolism

KW - Structure-Activity Relationship

U2 - 10.1021/acs.jmedchem.7b01484

DO - 10.1021/acs.jmedchem.7b01484

M3 - Journal article

C2 - 29451785

VL - 61

SP - 1951

EP - 1968

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -

ID: 225120334