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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2017 Jun 7

PMID 28586221

Citations 9

Authors

Katie L Strong

Matthew P Epplin

John Bacsa

Christopher J Butch

Pieter B Burger

David S Menaldino

Stephen F Traynelis

Dennis C Liotta

Affiliations

Soon will be listed here.

Abstract

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 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.

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