Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity

Fabao Zhao; Unai Atxabal; Sofia Mariottini; Feng Yi; James S. Lotti; Nirvan Rouzbeh; Na Liu; Lennart Bunch; Kasper B. Hansen; Rasmus P. Clausen

doi:10.1021/acs.jmedchem.1c01810

Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity

Fabao Zhao
, Unai Atxabal
, Sofia Mariottini
, Feng Yi
, James S. Lotti
, Nirvan Rouzbeh
, Na Liu
, Lennart Bunch
, Kasper B. Hansen
, Rasmus P. Clausen

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

10 Scopus citations

Abstract

NMDA receptors mediate glutamatergic neurotransmission and are therapeutic targets due to their involvement in a variety of psychiatric and neurological disorders. Here, we describe the design and synthesis of a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues 8a-s as agonists at the glycine (Gly) binding site in the GluN1 subunit, but not GluN3 subunits, of NMDA receptors. These novel analogues display highly variable potencies and agonist efficacies among the NMDA receptor subtypes (GluN1/2A-D) in a manner dependent on the GluN2 subunit. Notably, compound 8p is identified as a potent partial agonist at GluN1/2C (EC50 = 0.074 μM) with an agonist efficacy of 28% relative to activation by Gly and virtually no agonist activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists can modulate the activity of specific NMDA receptor subtypes by replacing the full endogenous agonists Gly or d-serine (d-Ser), thereby providing new opportunities in the development of novel therapeutic agents.

Original language	English
Pages (from-to)	734-746
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01810
State	Published - Jan 13 2022

Funding

The authors acknowledge financial support from the China Scholarship Council to F.Z. and the National Institutes of Health [NS097536, NS116055, GM103546] to K.B.H. The authors declare the following competing financial interest(s): K.B.H. is principal investigator on a research grant from Janssen Research and Development to the University of Montana. All other authors have no conflicts of interest to declare. Acknowledgments

Funder number
GM103546, NS097536
R01NS116055

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10.1021/acs.jmedchem.1c01810

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Zhao, F., Atxabal, U., Mariottini, S., Yi, F., Lotti, J. S., Rouzbeh, N., Liu, N., Bunch, L., Hansen, K. B., & Clausen, R. P. (2022). Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity. Journal of Medicinal Chemistry, 65(1), 734-746. https://doi.org/10.1021/acs.jmedchem.1c01810

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title = "Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity",

abstract = "NMDA receptors mediate glutamatergic neurotransmission and are therapeutic targets due to their involvement in a variety of psychiatric and neurological disorders. Here, we describe the design and synthesis of a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues 8a-s as agonists at the glycine (Gly) binding site in the GluN1 subunit, but not GluN3 subunits, of NMDA receptors. These novel analogues display highly variable potencies and agonist efficacies among the NMDA receptor subtypes (GluN1/2A-D) in a manner dependent on the GluN2 subunit. Notably, compound 8p is identified as a potent partial agonist at GluN1/2C (EC50 = 0.074 μM) with an agonist efficacy of 28\% relative to activation by Gly and virtually no agonist activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists can modulate the activity of specific NMDA receptor subtypes by replacing the full endogenous agonists Gly or d-serine (d-Ser), thereby providing new opportunities in the development of novel therapeutic agents.",

author = "Fabao Zhao and Unai Atxabal and Sofia Mariottini and Feng Yi and Lotti, \{James S.\} and Nirvan Rouzbeh and Na Liu and Lennart Bunch and Hansen, \{Kasper B.\} and Clausen, \{Rasmus P.\}",

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Zhao, F, Atxabal, U, Mariottini, S, Yi, F, Lotti, JS, Rouzbeh, N, Liu, N, Bunch, L, Hansen, KB & Clausen, RP 2022, 'Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity', Journal of Medicinal Chemistry, vol. 65, no. 1, pp. 734-746. https://doi.org/10.1021/acs.jmedchem.1c01810

TY - JOUR

T1 - Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity

AU - Zhao, Fabao

AU - Atxabal, Unai

AU - Mariottini, Sofia

AU - Yi, Feng

AU - Lotti, James S.

AU - Rouzbeh, Nirvan

AU - Liu, Na

AU - Bunch, Lennart

AU - Hansen, Kasper B.

AU - Clausen, Rasmus P.

PY - 2022/1/13

Y1 - 2022/1/13

N2 - NMDA receptors mediate glutamatergic neurotransmission and are therapeutic targets due to their involvement in a variety of psychiatric and neurological disorders. Here, we describe the design and synthesis of a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues 8a-s as agonists at the glycine (Gly) binding site in the GluN1 subunit, but not GluN3 subunits, of NMDA receptors. These novel analogues display highly variable potencies and agonist efficacies among the NMDA receptor subtypes (GluN1/2A-D) in a manner dependent on the GluN2 subunit. Notably, compound 8p is identified as a potent partial agonist at GluN1/2C (EC50 = 0.074 μM) with an agonist efficacy of 28% relative to activation by Gly and virtually no agonist activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists can modulate the activity of specific NMDA receptor subtypes by replacing the full endogenous agonists Gly or d-serine (d-Ser), thereby providing new opportunities in the development of novel therapeutic agents.

AB - NMDA receptors mediate glutamatergic neurotransmission and are therapeutic targets due to their involvement in a variety of psychiatric and neurological disorders. Here, we describe the design and synthesis of a series of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues 8a-s as agonists at the glycine (Gly) binding site in the GluN1 subunit, but not GluN3 subunits, of NMDA receptors. These novel analogues display highly variable potencies and agonist efficacies among the NMDA receptor subtypes (GluN1/2A-D) in a manner dependent on the GluN2 subunit. Notably, compound 8p is identified as a potent partial agonist at GluN1/2C (EC50 = 0.074 μM) with an agonist efficacy of 28% relative to activation by Gly and virtually no agonist activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists can modulate the activity of specific NMDA receptor subtypes by replacing the full endogenous agonists Gly or d-serine (d-Ser), thereby providing new opportunities in the development of novel therapeutic agents.

UR - https://www.scopus.com/pages/publications/85121917554

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DO - 10.1021/acs.jmedchem.1c01810

M3 - Article

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AN - SCOPUS:85121917554

SN - 0022-2623

VL - 65

SP - 734

EP - 746

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -

Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity

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