Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

Alex R. Maolanon; Rune Risgaard; Shuang Yan Wang; Yoran Snoep; Athanasios Papangelis; Feng Yi; David Holley; Anne F. Barslund; Niels Svenstrup; Kasper B. Hansen; Rasmus P. Clausen

doi:10.1021/acschemneuro.7b00117

Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

Alex R. Maolanon, Rune Risgaard, Shuang Yan Wang, Yoran Snoep, Athanasios Papangelis, Feng Yi, David Holley, Anne F. Barslund, Niels Svenstrup, Kasper B. Hansen, Rasmus P. Clausen^*

^*Corresponding author for this work

10 Citations (Scopus)

Abstract

A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

Original language	English
Journal	ACS Chemical Neuroscience
Volume	8
Issue number	8
Pages (from-to)	1681-1687
Number of pages	7
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.7b00117
Publication status	Published - 16 Aug 2017

Keywords

d -cycloserine
d -serine
Ionotropic glutamate receptor
NMDA
subtype selectivity
superagonist

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10.1021/acschemneuro.7b00117

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title = "Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites",

abstract = "A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.",

keywords = "d -cycloserine, d -serine, Ionotropic glutamate receptor, NMDA, subtype selectivity, superagonist",

author = "Maolanon, {Alex R.} and Rune Risgaard and Wang, {Shuang Yan} and Yoran Snoep and Athanasios Papangelis and Feng Yi and David Holley and Barslund, {Anne F.} and Niels Svenstrup and Hansen, {Kasper B.} and Clausen, {Rasmus P.}",

year = "2017",

month = aug,

day = "16",

doi = "10.1021/acschemneuro.7b00117",

language = "English",

volume = "8",

pages = "1681--1687",

journal = "ACS Chemical Neuroscience",

issn = "1948-7193",

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TY - JOUR

T1 - Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

AU - Maolanon, Alex R.

AU - Risgaard, Rune

AU - Wang, Shuang Yan

AU - Snoep, Yoran

AU - Papangelis, Athanasios

AU - Yi, Feng

AU - Holley, David

AU - Barslund, Anne F.

AU - Svenstrup, Niels

AU - Hansen, Kasper B.

AU - Clausen, Rasmus P.

PY - 2017/8/16

Y1 - 2017/8/16

N2 - A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

AB - A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

KW - d -cycloserine

KW - d -serine

KW - Ionotropic glutamate receptor

KW - NMDA

KW - subtype selectivity

KW - superagonist

U2 - 10.1021/acschemneuro.7b00117

DO - 10.1021/acschemneuro.7b00117

M3 - Letter

C2 - 28514141

AN - SCOPUS:85027413593

SN - 1948-7193

VL - 8

SP - 1681

EP - 1687

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

IS - 8

ER -

Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

Abstract

Keywords

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