Stereoselective synthesis of novel 2′-(S)-CCG-IV analogues as potent NMDA receptor agonists

Alex Maolanon; Athanasios Papangelis; David Kawiecki; Tung Chung Mou; Jed T. Syrenne; Feng Yi; Kasper B. Hansen; Rasmus P. Clausen

doi:10.1016/j.ejmech.2020.113099

Stereoselective synthesis of novel 2′-(S)-CCG-IV analogues as potent NMDA receptor agonists

Alex Maolanon
, Athanasios Papangelis
, David Kawiecki
, Tung Chung Mou
, Jed T. Syrenne
, Feng Yi
, Kasper B. Hansen
, Rasmus P. Clausen

Division of Biological and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

We developed a versatile stereoselective route for the synthesis of new 2′-(S)-CCG-IV analogues. The route allows for late stage diversification and thereby provides access to a great variety of conformationally restricted cyclopropyl glutamate analogues. A selection of the 2′-(S)-CCG-IV analogues were evaluated using two-electrode voltage-clamp electrophysiology at recombinant GluN1/GluN2A-D receptors, demonstrating that agonists can be developed with GluN2 subunit-dependent potency and agonist efficacy. We also describe a crystal structure of the GluN2A agonist binding domain in complex with 2′-butyl-(S)-CCG-IV that determines the position of 2′-substituents in (S)-CCG-IV agonists in the glutamate binding site and provides further insight to the structural determinants of their agonist efficacy. The stereoselective synthesis described here enables versatile and straight-forward modifications to diverse analogues of interest for the development of potent subtype-specific NMDA receptor agonists and other applications.

Original language	English
Article number	113099
Journal	European Journal of Medicinal Chemistry
Volume	212
DOIs	https://doi.org/10.1016/j.ejmech.2020.113099
State	Published - Feb 15 2021

Funding

We would like to thank Cindee Yates-Hansen and Gina Bullard for excellent technical assistance. The authors thank the Integrated Structural Biology Core Facility at University of Montana and the staff at the Advanced Photon System ( APS ), Argonne National Laboratory for their excellent beamline support. The use of APS is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-06-CH11357. We thank Dr. Hiro Furukawa for providing the DNA construct for expression and purification of the GluN2A ABD. K·B.H. is the principal investigator on a research grant from Janssen Research and Development to University of Montana. This project was supported by NIH-NINDS (NS097536) and NIH-NIGMS (GM103546).We would like to thank Cindee Yates-Hansen and Gina Bullard for excellent technical assistance. The authors thank the Integrated Structural Biology Core Facility at University of Montana and the staff at the Advanced Photon System (APS), Argonne National Laboratory for their excellent beamline support. The use of APS is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-06-CH11357. We thank Dr. Hiro Furukawa for providing the DNA construct for expression and purification of the GluN2A ABD. This project was supported by NIH- NINDS (NS097536) and NIH- NIGMS (GM103546).

Funders	Funder number
GM103546
R01NS097536
DE-AC02-06-CH11357
Argonne National Laboratory

Keywords

(carboxycyclopropyl)glycine
NMDA
Synthesis
X-ray crystallography

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10.1016/j.ejmech.2020.113099

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title = "Stereoselective synthesis of novel 2′-(S)-CCG-IV analogues as potent NMDA receptor agonists",

abstract = "We developed a versatile stereoselective route for the synthesis of new 2′-(S)-CCG-IV analogues. The route allows for late stage diversification and thereby provides access to a great variety of conformationally restricted cyclopropyl glutamate analogues. A selection of the 2′-(S)-CCG-IV analogues were evaluated using two-electrode voltage-clamp electrophysiology at recombinant GluN1/GluN2A-D receptors, demonstrating that agonists can be developed with GluN2 subunit-dependent potency and agonist efficacy. We also describe a crystal structure of the GluN2A agonist binding domain in complex with 2′-butyl-(S)-CCG-IV that determines the position of 2′-substituents in (S)-CCG-IV agonists in the glutamate binding site and provides further insight to the structural determinants of their agonist efficacy. The stereoselective synthesis described here enables versatile and straight-forward modifications to diverse analogues of interest for the development of potent subtype-specific NMDA receptor agonists and other applications.",

keywords = "(carboxycyclopropyl)glycine, NMDA, Synthesis, X-ray crystallography",

author = "Alex Maolanon and Athanasios Papangelis and David Kawiecki and Mou, \{Tung Chung\} and Syrenne, \{Jed T.\} and Feng Yi and Hansen, \{Kasper B.\} and Clausen, \{Rasmus P.\}",

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year = "2021",

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doi = "10.1016/j.ejmech.2020.113099",

language = "English",

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AU - Maolanon, Alex

AU - Papangelis, Athanasios

AU - Kawiecki, David

AU - Mou, Tung Chung

AU - Syrenne, Jed T.

AU - Yi, Feng

AU - Hansen, Kasper B.

AU - Clausen, Rasmus P.

PY - 2021/2/15

Y1 - 2021/2/15

N2 - We developed a versatile stereoselective route for the synthesis of new 2′-(S)-CCG-IV analogues. The route allows for late stage diversification and thereby provides access to a great variety of conformationally restricted cyclopropyl glutamate analogues. A selection of the 2′-(S)-CCG-IV analogues were evaluated using two-electrode voltage-clamp electrophysiology at recombinant GluN1/GluN2A-D receptors, demonstrating that agonists can be developed with GluN2 subunit-dependent potency and agonist efficacy. We also describe a crystal structure of the GluN2A agonist binding domain in complex with 2′-butyl-(S)-CCG-IV that determines the position of 2′-substituents in (S)-CCG-IV agonists in the glutamate binding site and provides further insight to the structural determinants of their agonist efficacy. The stereoselective synthesis described here enables versatile and straight-forward modifications to diverse analogues of interest for the development of potent subtype-specific NMDA receptor agonists and other applications.

AB - We developed a versatile stereoselective route for the synthesis of new 2′-(S)-CCG-IV analogues. The route allows for late stage diversification and thereby provides access to a great variety of conformationally restricted cyclopropyl glutamate analogues. A selection of the 2′-(S)-CCG-IV analogues were evaluated using two-electrode voltage-clamp electrophysiology at recombinant GluN1/GluN2A-D receptors, demonstrating that agonists can be developed with GluN2 subunit-dependent potency and agonist efficacy. We also describe a crystal structure of the GluN2A agonist binding domain in complex with 2′-butyl-(S)-CCG-IV that determines the position of 2′-substituents in (S)-CCG-IV agonists in the glutamate binding site and provides further insight to the structural determinants of their agonist efficacy. The stereoselective synthesis described here enables versatile and straight-forward modifications to diverse analogues of interest for the development of potent subtype-specific NMDA receptor agonists and other applications.

KW - (carboxycyclopropyl)glycine

KW - NMDA

KW - Synthesis

KW - X-ray crystallography

UR - https://www.scopus.com/pages/publications/85098177490

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DO - 10.1016/j.ejmech.2020.113099

M3 - Article

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AN - SCOPUS:85098177490

SN - 0223-5234

VL - 212

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 113099

ER -

Stereoselective synthesis of novel 2′-(S)-CCG-IV analogues as potent NMDA receptor agonists

Abstract

Funding

Keywords

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