11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors

Darius P Zlotos; Amal M Y Mohsen; Yasmine M Mandour; Mohamed A Marzouk; Ulrike Breitinger; Carmen Villmann; Hans-Georg Breitinger; Christoph Sotriffer; Anders A Jensen; Ulrike Holzgrabe

doi:10.1021/acs.jnatprod.9b00180

11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors

Darius P Zlotos, Amal M Y Mohsen, Yasmine M Mandour, Mohamed A Marzouk, Ulrike Breitinger, Carmen Villmann, Hans-Georg Breitinger, Christoph Sotriffer, Anders A Jensen, Ulrike Holzgrabe

2 Citations (Scopus)

Abstract

(11S)-11-Aminostrychnine (1) and N-[(11S)-strychnine-11-yl]propionamide (2) were synthesized and characterized as antagonists of homomeric α1 and heteromeric α1β glycine receptors in a functional fluorescence-based assay and a patch-clamp assay and in radioligand binding studies. The absolute configuration at C-11 of 1 was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptor showed a binding mode of compound 2 analogous to that of strychnine, explaining its high antagonistic potency. The findings identify the C-11 amide function of strychnine as a suitable linker group for the future development of dimeric strychnine analogues targeting glycine receptors. The findings extend the SAR of strychnine at glycine receptors.

Original language	English
Journal	Journal of Natural Products
Volume	82
Pages (from-to)	2332-2336
ISSN	0163-3864
DOIs	https://doi.org/10.1021/acs.jnatprod.9b00180
Publication status	Published - 23 Aug 2019

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Zlotos, D. P., Mohsen, A. M. Y., Mandour, Y. M., Marzouk, M. A., Breitinger, U., Villmann, C., Breitinger, H-G., Sotriffer, C., Jensen, A. A., & Holzgrabe, U. (2019). 11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors. Journal of Natural Products, 82, 2332-2336. https://doi.org/10.1021/acs.jnatprod.9b00180

Zlotos, DP, Mohsen, AMY, Mandour, YM, Marzouk, MA, Breitinger, U, Villmann, C, Breitinger, H-G, Sotriffer, C, Jensen, AA & Holzgrabe, U 2019, '11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors', Journal of Natural Products, vol. 82, pp. 2332-2336. https://doi.org/10.1021/acs.jnatprod.9b00180

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title = "11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors",

abstract = "(11S)-11-Aminostrychnine (1) and N-[(11S)-strychnine-11-yl]propionamide (2) were synthesized and characterized as antagonists of homomeric α1 and heteromeric α1β glycine receptors in a functional fluorescence-based assay and a patch-clamp assay and in radioligand binding studies. The absolute configuration at C-11 of 1 was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptor showed a binding mode of compound 2 analogous to that of strychnine, explaining its high antagonistic potency. The findings identify the C-11 amide function of strychnine as a suitable linker group for the future development of dimeric strychnine analogues targeting glycine receptors. The findings extend the SAR of strychnine at glycine receptors.",

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year = "2019",

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doi = "10.1021/acs.jnatprod.9b00180",

language = "English",

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T1 - 11-Aminostrychnine and N-(Strychnine-11-yl)propionamide

T2 - Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors

AU - Zlotos, Darius P

AU - Mohsen, Amal M Y

AU - Mandour, Yasmine M

AU - Marzouk, Mohamed A

AU - Breitinger, Ulrike

AU - Villmann, Carmen

AU - Breitinger, Hans-Georg

AU - Sotriffer, Christoph

AU - Jensen, Anders A

AU - Holzgrabe, Ulrike

PY - 2019/8/23

Y1 - 2019/8/23

N2 - (11S)-11-Aminostrychnine (1) and N-[(11S)-strychnine-11-yl]propionamide (2) were synthesized and characterized as antagonists of homomeric α1 and heteromeric α1β glycine receptors in a functional fluorescence-based assay and a patch-clamp assay and in radioligand binding studies. The absolute configuration at C-11 of 1 was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptor showed a binding mode of compound 2 analogous to that of strychnine, explaining its high antagonistic potency. The findings identify the C-11 amide function of strychnine as a suitable linker group for the future development of dimeric strychnine analogues targeting glycine receptors. The findings extend the SAR of strychnine at glycine receptors.

AB - (11S)-11-Aminostrychnine (1) and N-[(11S)-strychnine-11-yl]propionamide (2) were synthesized and characterized as antagonists of homomeric α1 and heteromeric α1β glycine receptors in a functional fluorescence-based assay and a patch-clamp assay and in radioligand binding studies. The absolute configuration at C-11 of 1 was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptor showed a binding mode of compound 2 analogous to that of strychnine, explaining its high antagonistic potency. The findings identify the C-11 amide function of strychnine as a suitable linker group for the future development of dimeric strychnine analogues targeting glycine receptors. The findings extend the SAR of strychnine at glycine receptors.

U2 - 10.1021/acs.jnatprod.9b00180

DO - 10.1021/acs.jnatprod.9b00180

M3 - Journal article

C2 - 31385511

SN - 0163-3864

VL - 82

SP - 2332

EP - 2336

JO - Journal of Natural Products

JF - Journal of Natural Products

ER -

11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors

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