The Structure–Activity
Relationship of a Tetrahydroisoquinoline
Class of <i>N</i>‑Methyl‑d‑Aspartate
Receptor Modulators that Potentiates GluN2B-Containing <i>N</i>‑Methyl‑d‑Aspartate Receptors
Katie
L. Strong
Matthew P. Epplin
John Bacsa
Christopher J. Butch
Pieter B. Burger
David S. Menaldino
Stephen F. Traynelis
Dennis C. Liotta
10.1021/acs.jmedchem.7b00239.s002
https://acs.figshare.com/articles/dataset/The_Structure_Activity_Relationship_of_a_Tetrahydroisoquinoline_Class_of_i_N_i_Methyl_d_Aspartate_Receptor_Modulators_that_Potentiates_GluN2B-Containing_i_N_i_Methyl_d_Aspartate_Receptors/5144152
We have identified a series of positive
allosteric NMDA receptor
(NMDAR) modulators derived from a known class of GluN2C/D-selective
tetrahydroisoquinoline analogues that includes CIQ. The prototypical
compound of this series contains a single isopropoxy moiety in place
of the two methoxy substituents present in CIQ. Modifications of this
isopropoxy-containing scaffold led to the identification of analogues
with enhanced activity at the GluN2B subunit. We identified molecules
that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C,
and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations
of agonist. Multiple compounds potentiate the response of NMDARs with
submicromolar EC<sub>50</sub> values. Analysis of enantiomeric pairs
revealed that the <i>S</i>-(−) enantiomer is active
at the GluN2B, GluN2C, and/or GluN2D subunits, whereas the <i>R</i>-(+) enantiomer is only active at GluN2C/D subunits. These
results provide a starting point for the development of selective
positive allosteric modulators for GluN2B-containing receptors.
2017-06-06 00:00:00
GluN 2C NMDARs
GluN 2B subunit
enantiomeric pairs
Multiple compounds potentiate
CIQ
methoxy substituents
GluN 2B receptors
GluN 2B GluN 2B
isopropoxy moiety
isopropoxy-containing scaffold
GluN 2B GluN 2C
GluN 2C subunits
2D
allosteric modulators
allosteric NMDA receptor
GluN 2C tetrahydroisoquinoline analogues
submicromolar EC 50 values
Tetrahydroisoquinoline Class