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Small-molecule probes for augmenting D5 receptor signaling

Award Number: R01MH132019
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Small-molecule probes for augmenting D5 receptor signaling - Project Summary Cognitive impairment is a core feature of many neuropsychiatric disorders that directly correlates with functional outcome for patients. Current treatment options are inadequate and there is a need for novel therapeutic strategies. The dopamine D1-like receptor family (D1 and D5 receptors) has been proposed as a potential target for improving cognitive function. Clinical studies with D1/D5 full agonists have shown promising efficacy, but these compounds suffer from significant drawbacks related to adverse effect profiles. The lack of selective ligands as well as considerable spatial overlap between the D1 and D5 receptors have made it difficult to determine which receptor is responsible for specific efficacy and adverse effect features of the nonselective agonists. There have been efforts to develop selective tools for D1 receptors but, to our knowledge, there have been no formal efforts to identify D5-selective compounds. Recent research from our group and others has shown that the D5 receptor plays a critical role in cognitive function, particularly in cognitive domains significantly disrupted in neuropsychiatric disorders. Additionally, multiple D5-selective signaling pathways relevant for neural function have been identified. Unfortunately, further experimentation to determine the role of the D5 receptor in neurobiology has been hindered by the lack of selective ligands. In this application, we propose to design and synthesize D5-selective chemical probes. Due to the high degree of homology between the D5 and D1 orthosteric binding sites, we will focus on allosteric modulators. Once selectivity for D5 receptors over D1 receptors has been established using cAMP induction assays, potency on cell-based assays of D5-specific signaling cascades will be determined. Compounds shown to be potent and selective will then undergo in vitro screening for metabolic stability and counterscreening against a broad panel of receptors and ion channels. Compounds that are found to be metabolically stable with minimal off-target binding, will be tested in vivo to determine if they have sufficient plasma and brain exposure to engage the D5 receptor and advance to pharmacodynamic assays. Finally, compounds will be tested to determine their ability to induce BDNF expression in the prefrontal cortex, a known effect of signaling through the D5 receptor. Once optimized and characterized, these D5-selective probes will allow us to further characterize the role of the D5 receptor in neural function and determine if it is a viable therapeutic target.


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 = $707,455 )
2025	2025	THE LIEBER INSTITUTE	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	3	11/20/2024	NON-COMPETING CONTINUATION	$707,455
														Subtotal = $707,455

Issue Date FY: 2024 ( Subtotal = $837,713 )
2024	2024	THE LIEBER INSTITUTE	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	001	2	8/19/2024	NON-COMPETING CONTINUATION	$83,771
2024	2024	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	2	11/29/2023	NON-COMPETING CONTINUATION	$753,942
														Subtotal = $837,713

Issue Date FY: 2023 ( Subtotal = $837,713 )
2023	2023	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	12/23/2022	NEW	$837,713
														Subtotal = $837,713

Grand Total All Awards = $2,382,881

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Small-molecule probes for augmenting D5 receptor signaling

Award Number: R01MH132019

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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