Strong, Katie L. Epplin, Matthew P. Bacsa, John Butch, Christopher J. Burger, Pieter B. Menaldino, David S. Traynelis, Stephen F. Liotta, Dennis C. 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 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. 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 2017-06-06
    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
10.1021/acs.jmedchem.7b00239.s002