Synthesis and Structure Activity Relationship of Tetrahydroisoquinoline-Based Potentiators of GluN2C and GluN2D Containing N-Methyl-d-aspartate Receptors

Abstract

We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the conversion of acyclic amides to the corresponding tetrahydroisoquinoline containing analogs. Compounds were evaluated using both two electrode voltage clamp recordings from Xenopus laevis oocytes and imaging of mammalian BHK cells loaded with Ca2+-sensitive dyes. The most potent analogues had EC50 values of 300 nM and showed over 2-fold potentiation of the response to maximally effective concentrations of glutamate and glycine, but had no effect on responses from NMDA receptors containing the GluN2A or GluN2B subunits, AMPA, kainate, GABA, or glycine receptors or a variety of other potential targets. These compounds represent a potent class of small molecule subunit-selective potentiators of NMDA receptors.

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

“…Previously published compound 86 with a methoxy group in the R 1 position 61 was selective for GluN2C and GluN2D subunits. When the methoxy group on the C-ring was replaced with an ethoxy group as in compound 87 , potentiation was observed at the GluN2B subunit in addition to GluN2C and GluN2D.…”

“…Tetrahydroisoquinoline-containing compounds selectively enhance the response of recombinant and native GluN2C- and GluN2D-containing NMDARs 58,59 to maximally effective concentrations of agonist with EC 50 values between 5–10 μM 60,61 . The naphthalene derivative 9-cyclopylphenanthrene-3-carboxylic acid (UBP-710, Figure 1) potentiates GluN2A- and GluN2B-containing receptors at 100 μM and inhibits GluN2C and GluN2D receptors at higher concentrations.…”

“…60,61 CIQ is selective for GluN2C- and GluN2D-containing NMDARs over GluN2A- and GluN2B-containing NMDARs and has no effect on AMPA or kainate receptors. An extensive SAR was described, and the most potent compounds in the series had EC 50 values of 300 nM at GluN2C and GluN2D subunits.…”

“…An extensive SAR was described, and the most potent compounds in the series had EC 50 values of 300 nM at GluN2C and GluN2D subunits. 61 During our initial exploration of the SAR of this series of GluN2C/GluN2D-selective positive allosteric modulators ( 1 ), we discovered a single compound ( 2 ) that displayed activity not just at GluN2C and GluN2D subunits, but also at the GluN2B subunit (Figure 2). Compound 2 resulted from the replacement of the dimethoxy groups in CIQ ( 1 ) with a single isopropoxy group.…”

Novel PAMs Targeting NMDAR GluN2A Subunit

“…Recent years have seen major advances in discovery of highly selective negative allosteric modulators (NAMs) of NMDARs that contain specific subunits, including selective GluN2B (Menniti et al, 1997; Williams, 1993; Yue et al, 2015) and GluN2C/2D (Zhu and Paoletti, 2015). Investigators interested in increasing NMDAR signaling are now taking the first steps toward developing highly selective PAMs of NMDARs with defined subunit compositions (Jambrina et al, 2016; Khatri et al, 2014; Santangelo Freel et al, 2013; Zimmerman et al, 2014). This approach has been highly successful in selectively increasing activity of other ligand-gated ion channels (Taly et al, 2014) and G protein-coupled receptors (GPCRs) (Conn et al, 2014).…”