A Novel Positive Allosteric Modulator of GluN1/3 NMDA Receptors

Author

Samuel A. Galindo, The University Of MontanaFollow

Year of Award

2025

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Neuroscience

Department or School/College

Division of Biological Sciences

Committee Chair

Kasper B. Hansen

Commitee Members

Kasper B. Hansen, Andrew Rau, Katie Holick

Keywords

NMDA receptor, Positive Allosteric Modulator, Glutamate Receptor, Neuropharmacology, Ion Channel, Electrophysiology

Subject Categories

Molecular and Cellular Neuroscience | Neuroscience and Neurobiology

Abstract

The GluN3-containing (GluN1/3) N-methyl-D-aspartate (NMDA) receptors are glycine activated ligand-gated ion channels that are members of the family of excitatory ionotropic glutamate receptors. Compared to the glycine/glutamate-activated GluN2- containing NMDA receptors (GluN1/2), which have been extensively studied, the GluN1/3 receptors are poorly understood, but are implicated in neuronal processes related to synaptic maturation and plasticity. GluN1/3 receptors are also implicated in a variety of neurological diseases. In addition to their poor understanding, we lack proper pharmacological tools for the study and modulation of these GluN1/3 receptors. In this study, we evaluate the activity and mechanism of action for AIMS-129 as a novel positive allosteric modulator (PAM) of GluN1/3A and GluN1/3B receptors, with EC50 values of 15 μM and 18 µM, respectively. AIMS-129 maximally potentiates GluN1/3A and GluN1/3B receptors to 214% and 479%, respectively, compared to responses from glycine alone. AIMS-129 stabilizes the glycine-bound, active conformation of GluN1/3 receptors and slows receptor deactivation time. AIMS-129 does not have the capability to act as an agonist and does not act competitively with glycine or D-serine agonists. Thus, AIMS-129 is classified as the first compound in a novel class of GluN3-selective PAMs and provides a new pharmacological compound that will facilitate future studies of GluN1/3 receptors and their physiological roles in normal brain function and disease.

Recommended Citation

Galindo, Samuel A., "A Novel Positive Allosteric Modulator of GluN1/3 NMDA Receptors" (2025). Graduate Student Theses, Dissertations, & Professional Papers. 12514.
https://scholarworks.umt.edu/etd/12514