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Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptors 2 & 3 (mGlu2/3) for the Treatment of Depression

Award Number: R43MH122063
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/05/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptors 2 & 3 (mGlu2/3) for the Treatment of Depression - SUMMARY Treatment-resistant depression (TRD) affects 20-30% of major depressive disorder (MDD) patients and is defined as a failure to respond to at least two adequate rounds of treatment with standard of care antidepressants. TRD represents a substantial unmet medical need, requiring novel treatments with rapid and sustained antidepressant activity and good safety and tolerability profiles. (S)-Ketamine (Spravato, Esketamine) was recently approved for the treatment of TRD; however, it has several adverse side effects including sedation, dissociative effects, and abuse liability. The precise mechanism of action (MOA) of ketamine remains unclear; while described as a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, it has additional non- NMDAR effects. In humans, ketamine is rapidly metabolized and some metabolites, such as (2R,6R)- hydroxynorketamine (HNK), have rapid antidepressant-like activity in rodent models. The antidepressant-like activity of HNK is partially mediated through metabotropic glutamate receptor subtype 2 (mGlu2). Thus, we propose that negative allosteric modulation of mGlu2/3 represents a promising new strategy to treat TRD. Our rationale is four-fold: (1) mGlu2/3 receptors are expressed in the forebrain regions affected in depression, with particular enrichment in the medial prefrontal cortex, hippocampus and medial habenula, (2) inhibition of mGlu2/3 leads to molecular and cellular changes similar to those caused by ketamine, including α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor potentiation, brain-derived neurotrophic factor (BDNF) release, activation of mammalian target of rapamycin (mTOR) and ultimately synaptic remodeling, (3) mGlu2/3 orthosteric antagonists produce ketamine-like behavioral effects with sustained efficacy in multiple rodent procedures that model aspects of depression, and (4) the antidepressant-like activity of the ketamine metabolite (2R,6R)-HNK in rodent models is partially mediated by mGlu2. Thus, mGlu2/3 negative allosteric modulators (NAMs) are predicted to produce antidepressant effects similar to ketamine without the psychotomimetic side effects. Our objective is to advance a mGlu2/3 NAM into preclinical development and IND-enabling studies. To this end, we have identified a lead and a backup mGlu2/3 NAM with excellent drug-like properties. The specific aims are the following: (1) Determine the efficacy of our lead mGlu2/3 NAM in the rodent Probabilistic Reward Task (PRT) and Effort-related Choice (ERC) task after acute oral dosing; and (2) Determine target engagement of our lead mGlu2/3 NAM in vivo. On completion of this Phase I STTR, we will be able to determine if the lead compound and/or the backup have the efficacy and pharmacological profile to be advanced into preclinical development, which would become the basis of a Phase II application. Hence, the studies proposed here are important precedents to support a future clinical program for MDD and TRD.


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: 2024 ( Subtotal = -$92,313 )
2024	2021	CAMINO PHARMA LLC	7161 ROCK VALLEY CT	SAN DIEGO	CA	92122	SAN DIEGO	USA	Mental Health Research Grants	000	2	12/14/2023	NON-COMPETING CONTINUATION	-$92,313
														Subtotal = -$92,313

Issue Date FY: 2021 ( Subtotal = $449,453 )
2021	2021	CAMINO PHARMA, LLC	7161 ROCK VALLEY CT	SAN DIEGO	CA	92122	SAN DIEGO	USA	Mental Health Research Grants	000	2	6/24/2021	NON-COMPETING CONTINUATION	$449,453
														Subtotal = $449,453

Issue Date FY: 2020 ( Subtotal = $469,863 )
2020	2020	CAMINO PHARMA, LLC	7161 ROCK VALLEY CT	SAN DIEGO	CA	92122	SAN DIEGO	USA	Mental Health Research Grants	000	1	6/5/2020	NEW	$469,863
														Subtotal = $469,863

Grand Total All Awards = $827,003

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Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptors 2 & 3 (mGlu2/3) for the Treatment of Depression

Award Number: R43MH122063

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/05/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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