The Structure Activity Relationship of a Tetrahydroisoquinoline Class of N-Methyl-D-Aspartate Receptor Modulators that Potentiates GluN2B-Containing N-Methyl-D-Aspartate Receptors
| Autor: | Pieter B. Burger, Stephen F. Traynelis, Christopher J. Butch, David S. Menaldino, Matthew P. Epplin, Katie L. Strong, Dennis C. Liotta, John Bacsa |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist Models Molecular Stereochemistry medicine.drug_class Allosteric regulation Administration Oral Crystallography X-Ray Receptors N-Methyl-D-Aspartate Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Allosteric Regulation Tetrahydroisoquinolines Drug Discovery medicine Structure–activity relationship Moiety Humans Receptor Dose-Response Relationship Drug Molecular Structure Chemistry Tetrahydroisoquinoline 030104 developmental biology Microsomes Liver Molecular Medicine NMDA receptor Enantiomer 030217 neurology & neurosurgery |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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