Wednesday, July 2, 2025 7/2/2025

Structural and functional investigation of allosteric NMDA receptor modulation

Award Number: R01NS097536
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Structural and functional investigation of allosteric NMDA receptor modulation - NMDA-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system (CNS) and play critical roles in brain functions. Aberrant NMDA receptor signaling is implicated in many CNS diseases, and NMDA receptors are receiving widespread interest as therapeutic targets. Although it has proven difficult to translate preclinical findings into clinical efficacy, the many NMDA receptor ligands from these studies have created a valuable pharmacological toolbox that continues to support neuroscience research. Most NMDA receptors are composed of two glycine-binding GluN1 and two glutamate-binding GluN2 subunits. There are four different GluN2 subunits (GluN2A-D) that endow NMDA receptors with distinct functional properties and different developmental and regional expression in the CNS. Selective modulation of NMDA receptors that contain a specific GluN2 subunit can therefore target a subset of receptor subtypes expressed in disease-relevant neuronal populations. NMDA receptors require simultaneous binding of glycine (or D-serine) to GluN1 and glutamate to GluN2 for activation, but mainly rely on synaptic release of glutamate for activation in the CNS, since extracellular glycine (or D-serine) is continuously present. Thus, glutamate binding to GluN2 primarily mediates phasic activation of synaptic NMDA receptors, while agonist occupancy at GluN1 can modulate response amplitude. We will investigate two distinct modes of NMDA receptor modulation, both of which display GluN2 subunit-selectivity and affect the GluN1 agonist binding site to modulate NMDA receptor responses. In Aim 1, we will define binding contacts and mechanism of action for a new class of GluN2A-selective negative allosteric modulators that bind the subunit interface between GluN1 and GluN2A agonist binding domains (ABDs) to negatively modulate agonist binding to GluN1. In Aim 2, we will determine the structural basis for GluN2 subunit-specific activity of novel glycine site agonists with remarkably high potency and unprecedented variation in agonist efficacy among NMDA receptor subtypes. By replacing endogenous glycine or D-serine, these GluN2-dependent agonists can modulate NMDA receptors when activated by synaptic glutamate release. In Aim 3, we will modulate neuronal NMDA receptors in acute rodent brain slices using novel GluN2A-selective NAMs and GluN1 agonists. NMDA receptor-positive neurons in the adult CNS express at least two different GluN2 subunits and many NMDA receptors are assembled with two different GluN2 subunits (i.e. triheteromeric receptors). We will evaluate the activity of the novel modulators at recombinant triheteromeric NMDA receptor subtypes (GluN1/2A/2B, GluN1/2B/2D, and GluN1/2A/2C) and at native NMDA receptors in distinct neuronal populations with defined expression of these GluN2 subunit combinations. These investigations will uncover previously unrecognized features of NMDA receptor modulation and provide new avenues for basic and translational research, as well as facilitate the development of novel therapeutic agents.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $329,400 )
2025	2025	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	11/15/2024	NON-COMPETING CONTINUATION	$329,400
														Subtotal = $329,400

Issue Date FY: 2024 ( Subtotal = $353,080 )
2024	2024	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	12/13/2023	NON-COMPETING CONTINUATION	$327,600
2024	2024	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	4/23/2024	NON-COMPETING CONTINUATION	$25,480
														Subtotal = $353,080

Issue Date FY: 2023 ( Subtotal = $344,224 )
2023	2023	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	11/15/2022	NON-COMPETING CONTINUATION	$309,802
2023	2023	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	7	1/31/2023	NON-COMPETING CONTINUATION	$34,422
2023	2022	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	11/9/2022	COMPETING CONTINUATION	$6,480
2023	2020	UNIVERSITY OF MONTANA	32 CAMPUS DR	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/9/2022	NON-COMPETING CONTINUATION	-$6,480
														Subtotal = $344,224

Issue Date FY: 2022 ( Subtotal = $371,776 )
2022	2022	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	11/18/2021	COMPETING CONTINUATION	$371,776
2022	2020	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $371,776

Issue Date FY: 2020 ( Subtotal = $317,188 )
2020	2020	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/18/2020	NON-COMPETING CONTINUATION	$317,188
														Subtotal = $317,188

Issue Date FY: 2019 ( Subtotal = $317,188 )
2019	2019	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/3/2019	NON-COMPETING CONTINUATION	$317,188
														Subtotal = $317,188

Issue Date FY: 2018 ( Subtotal = $317,188 )
2018	2018	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/16/2018	NON-COMPETING CONTINUATION	$317,188
														Subtotal = $317,188

Issue Date FY: 2017 ( Subtotal = $317,188 )
2017	2017	UNIVERSITY OF MONTANA	32 CAMPUS DR MAIN HALL	MISSOULA	MT	59812	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/1/2017	NON-COMPETING CONTINUATION	$317,188
														Subtotal = $317,188

Issue Date FY: 2016 ( Subtotal = $317,188 )
2016	2016	UNIVERSITY OF MONTANA	**	MISSOULA	MT	59801	MISSOULA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/18/2016	NEW	$317,188
														Subtotal = $317,188

Grand Total All Awards = $2,984,420

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Structural and functional investigation of allosteric NMDA receptor modulation

Award Number: R01NS097536

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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