Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists

Amal M Y Mohsen; Yasmine M Mandour; Edita Sarukhanyan; Ulrike Breitinger; Carmen Villmann; Maha M Banoub; Hans-Georg Breitinger; Thomas Dandekar; Ulrike Holzgrabe; Christoph Sotriffer; Anders A Jensen; Darius P Zlotos

doi:10.1021/acs.jnatprod.6b00479

Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists

Amal M Y Mohsen, Yasmine M Mandour, Edita Sarukhanyan, Ulrike Breitinger, Carmen Villmann, Maha M Banoub, Hans-Georg Breitinger, Thomas Dandekar, Ulrike Holzgrabe, Christoph Sotriffer, Anders A Jensen, Darius P Zlotos

6 Citations (Scopus)

Abstract

A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [(3)H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.

Original language	English
Journal	Journal of Natural Products
Volume	79
Issue number	12
Pages (from-to)	2997–3005
Number of pages	9
ISSN	0163-3864
DOIs	https://doi.org/10.1021/acs.jnatprod.6b00479
Publication status	Published - 23 Dec 2016

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Mohsen, A. M. Y., Mandour, Y. M., Sarukhanyan, E., Breitinger, U., Villmann, C., Banoub, M. M., Breitinger, H.-G., Dandekar, T., Holzgrabe, U., Sotriffer, C., Jensen, A. A., & Zlotos, D. P. (2016). Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists. Journal of Natural Products, 79(12), 2997–3005. https://doi.org/10.1021/acs.jnatprod.6b00479

Mohsen, AMY, Mandour, YM, Sarukhanyan, E, Breitinger, U, Villmann, C, Banoub, MM, Breitinger, H-G, Dandekar, T, Holzgrabe, U, Sotriffer, C, Jensen, AA & Zlotos, DP 2016, 'Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists', Journal of Natural Products, vol. 79, no. 12, pp. 2997–3005. https://doi.org/10.1021/acs.jnatprod.6b00479

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title = "Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists",

abstract = "A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [(3)H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.",

author = "Mohsen, {Amal M Y} and Mandour, {Yasmine M} and Edita Sarukhanyan and Ulrike Breitinger and Carmen Villmann and Banoub, {Maha M} and Hans-Georg Breitinger and Thomas Dandekar and Ulrike Holzgrabe and Christoph Sotriffer and Jensen, {Anders A} and Zlotos, {Darius P}",

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AU - Mohsen, Amal M Y

AU - Mandour, Yasmine M

AU - Sarukhanyan, Edita

AU - Breitinger, Ulrike

AU - Villmann, Carmen

AU - Banoub, Maha M

AU - Breitinger, Hans-Georg

AU - Dandekar, Thomas

AU - Holzgrabe, Ulrike

AU - Sotriffer, Christoph

AU - Jensen, Anders A

AU - Zlotos, Darius P

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N2 - A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [(3)H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.

AB - A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [(3)H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.

U2 - 10.1021/acs.jnatprod.6b00479

DO - 10.1021/acs.jnatprod.6b00479

M3 - Journal article

C2 - 27966945

SN - 0163-3864

VL - 79

SP - 2997

EP - 3005

JO - Journal of Natural Products

JF - Journal of Natural Products

IS - 12

ER -

Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists

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