The Structure-Activity Relationship of a Tetrahydroisoquinoline Class of N-Methyl-D-Aspartate Receptor Modulators that Potentiates GIuN2B-Containing N-Methyl-D-Aspartate Receptors

作者：Strong Katie L; Epplin Matthew P; Bacsa John; Butch Christopher J; Burger Pieter B; Menaldino David S; Traynelis Stephen F^*; Liotta Dennis C^*

来源：Journal of Medicinal Chemistry, 2017, 60(13): 5556-5585.

DOI：10.1021/acs.jmedchem.7b00239

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.

• 出版日期2017-7-13