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

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 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.

Negative allosteric modulation of GluN1/GluN3 NMDA receptors

“…This degree of selectivity should allow use of EU1180-438 as a tool to determine whether specific neuronal functions or behaviors involve GluN3-containing receptors, with the caveat that some effects could reflect reduction in nicotinic receptor function, which can be easily controlled for by available pharmacological tools. The inhibitor EU1180-438 acts in a voltage-independent and non-competitive fashion, and has some similarities in the scaffold with the tetrahydroisoquinolines that can act on GluN1/GluN2 NMDA receptors (Santangelo Freel et al, 2013;Strong et al, 2017) with structural determinants in the GluN2 pre-M1 helix (Kevin K. Ogden & Traynelis, 2011). Given the specificity for GluN1/GluN3, we anticipate that EU1180-438 interacts primarily with GluN3 residues rather than GluN1 residues, and speculate that the pre-M1 region is a likely target of action.…”

Biased modulators of NMDA receptors control channel opening and ion selectivity

“…We repeated these experiments using a different set of biionic solutions that allowed the determination of the Ca 2+ /Cs + permeability ratio in lower Ca 2+ (0, 1.8 mM), which confirmed that 50 μM EU1622-14 reduced the relative permeability to Ca 2+ (Supplementary Figure 7). To determine whether this was a feature in general of NMDAR positive allosteric modulators, we evaluated compound (−)-EU1180-325 (Compound 3, compound S-(−)-2 in Strong et al 2017), which potentiated the response to maximally effective glutamate and glycine in GluN1/GluN2B, GluN1/GluN2C, and GluN1/GluN2D receptors expressed in HEK cells in a similar fashion to EU1622-14 18 . We found no detectable change in unitary currents determined from variance analysis ( Supplementary Table 4), and no detectable change in the permeability ratio for Ca 2+ and Na + (as determined by the biionic method, Supplementary Figure 7), despite robust enhancement of the NMDAR response (Supplementary Table 9).…”

“…NMDARs are tetrameric assemblies of two glycine-binding GluN1 and two glutamate-binding GluN2 subunits, of which there are four subtypes GluN2A-2D 1 . The recent development of subunit-selective NMDAR positive allosteric modulators should allow cell-type-or circuit-specific modulation due to spatiallydistinct GluN2 expression, without global NMDAR overactivation [13][14][15][16][17][18][19][20] . However, while positive allosteric modulators act only when agonist is present to enhance NMDAR function, there remains a risk for overactivation at some synapses.…”

The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor

“…ABBREVIATIONS: ABD, agonist binding domain; ATD, amino terminal domain; ER, endoplasmic reticulum; MD, molecular dynamics; NAMFIS, nuclear magnetic resonance analysis of molecular flexibility in solution; NMDA, N-methyl-D-aspartate; NMDA-R, N-methyl-D-aspartate receptor; NOE, nuclear Overhauser effect; NOESY, nuclear Overhauser effect spectroscopy; PDB, Protein Data Bank; PYD-106, methyl 4-(3-acetyl-4hydroxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate; RMSD, root-mean-square deviation; ROC, receiver operating characteristic; SAR, structure-activity relationship; XP, extra precision. Costa et al, 2010;Mosley et al, 2010;Mullasseril et al, 2010;Acker et al, 2011;Santangelo Freel et al, 2013;Hackos et al, 2016;Strong et al, 2017) and include the GluN2C-selective pyrrolidinones (Zimmerman et al, 2014). The identification of new ligands acting on GluN2A, C, and D has led to the elucidation of potentially new modulator binding sites, including the pre-M1/M1 helix of GluN2C/D [CIQ (Ogden et al, 2014;Swanger et al, 2017)], the membrane proximal face of the agonist binding domain [QNZ-46 andDQP-1105 (Acker et al, 2011;Hansen and Traynelis, 2011)] and the dimer interface of the GluN1/GluN2A ligand binding domain [TCN-201 (Hansen et al, 2012) and GNE compounds (Hackos and Hanson, 2017)].…”