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Distinct GluN1 and GluN2 Structural Determinants for Subunit-Selective Positive Allosteric Modulation of
Katie L Strong1,2, Matthew P Epplin2, Kevin K Ogden1
1Department of Pharmacology, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, United States.
ACS Chemical Neuroscience
|December 16, 2020
Summary
New N-Methyl-D-aspartate receptor (NMDAR) positive allosteric modulators (PAMs) show expanded subunit selectivity. These novel tetrahydroisoquinoline analogues offer distinct pharmacological profiles for potential therapeutic applications in neurological disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- N-Methyl-D-aspartate receptors (NMDARs) are crucial for fast excitatory synaptic transmission in the central nervous system.
- NMDAR hypofunction is implicated in several neurological disorders, driving interest in therapeutic NMDAR positive allosteric modulators (PAMs).
Purpose of the Study:
- To develop novel NMDAR PAMs with expanded subunit selectivity beyond GluN2C/GluN2D.
- To investigate the structure-activity relationships and distinct binding sites of novel NMDAR PAM enantiomers.
Main Methods:
- Chemical modification of tetrahydroisoquinoline scaffold to generate new NMDAR PAM analogues.
- Electrophysiological evaluation of compound activity on recombinant and synaptic NMDARs containing various GluN2 subunits.
- Site-directed mutagenesis and molecular modeling to identify structural determinants of PAM action.
Main Results:
- Modified tetrahydroisoquinoline analogues demonstrated activity at NMDARs containing GluN2A, GluN2B, GluN2C, and GluN2D subunits.
- (S)-enantiomers showed broader activity across NMDAR subtypes, while (R)-enantiomers were more selective for GluN2C/GluN2D.
- Distinct structural determinants in GluN1 and GluN2D subunits were identified for the differential actions of (S) and (R) enantiomers, suggesting dual binding sites.
Conclusions:
- Novel NMDAR PAMs with tunable subunit selectivity have been developed.
- The distinct pharmacological profiles of (S) and (R) enantiomers arise from interactions with different sites within the NMDAR structure.
- These findings provide a foundation for developing targeted NMDAR-based therapeutics.
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