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The Structure–Activity Relationship of a Tetrahydroisoquinoline Class of N‑Methyl‑d‑Aspartate Receptor Modulators that Potentiates GluN2B-Containing N‑Methyl‑d‑Aspartate Receptors

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journal contribution
posted on 06.06.2017 by Katie L. Strong, Matthew P. Epplin, John Bacsa, Christopher J. Butch, Pieter B. Burger, David S. Menaldino, Stephen F. Traynelis, Dennis C. Liotta
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 EC50 values. Analysis of enantiomeric pairs revealed that the S-(−) enantiomer is active at the GluN2B, GluN2C, and/or GluN2D subunits, whereas the R-(+) 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.