Development of high-affinity and selective ligands as a pharmacological tool for the dopamine D4 receptor (D4R) subtype variants

Active Project Grant Awarded Last action

Award ID
DP1DA058385
Recipient
Awarding agency
Obligated
$3,531,300

Award facts

Assistance listing
93.279 Drug Use and Addiction Research Programs
Completion date 72% complete
Place of performance
High Point, NC 27268, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision-making. The human DRD4 gene is highly polymorphic, with different variants associated with various neuropsychiatric disorders. In particular, vntr variants (the three major ones are termed D4.2R, D4.4R, and D4.7R) are differentially associated with adhd and substance use disorders, with the D4.7R reliably associated with increased prevalence of adhd and substance use disorders (SUDS). Determining precise physiological roles of D4R signaling as well as understanding the consequences of D4R variants in contributing to disease states has been hampered by the lack of suitable compounds with high affinity, sufficient selectivity, characterized agonist-antagonist responses, and/or suitable in vivo activity. Currently there are no known compounds with differential activity at D4R variants. Therefore, we seek to develop new, optimized D4R ligands with variant-specific activity to expand our understanding of D4R function and in the development of potential therapeutic compounds. D4.7R has altered ability to heteromerize with dopamine D2 receptors (D2RS) or A2A adrenergic receptors (A2ARS), when compared to the more common D4.4R. Our team has discovered that D4R agonist a-412997 produces differential signaling at D4.7R or D4.4R heteromerized with D2R or A2AR, and differential signaling at GAI1 versus GAO1. We will leverage our existing library of a-412997 analogs, and create new rationally designed analogs, to identify new pharmacological tools will have the potential to surmount current limitations on the understanding of the functional significance of D4R vntr polymorphisms. Novel D4R ligands also hold the potential to be used as pharmacotherapeutics for SUD. Since there are no FDA-approved medications for the treatment of psychostimulant use disorders, and no FDA-approved medications selective for D4R, novel pharmacological tools targeting D4R variants can address multiple needs. The proposed research seeks to design, synthesize, and evaluate new ligands using computational modeling approaches that exploit underexplored regions within the D4R protein structure to develop selective D4.2R, D4.4R, and D4.7R ligands.

Transactions

Action Obligated Date
Amendment $447,000
Amendment $447,000
Amendment $44,700
Amendment $44,700
Amendment $402,300
Amendment $402,300
Amendment $402,300
Amendment $447,000
Amendment $447,000
Original award $447,000

Subawards

Subrecipient Amount Awarded
Rowan University The ultimate goal of these experiments is to identify new treatments for ADHD and substance use disorders. This study focuses on comprehensively evaluating lead… $101,624
University Of Florida Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants - PROJECT SUMMARY/ABSTRACT… $56,071
Rowan University The ultimate goal of these experiments is to identify new treatments for ADHD and substance use disorders. This study focuses on comprehensively evaluating lead… $91,964
Loma Linda University New sub-award to Loma Linda University $70,000
Rowan University The ultimate goal of these experiments is to identify new treatments for ADHD and substance use disorders. This study focuses on comprehensively evaluating lead… -$25,760
University Of Florida Deobligation -$27,830
The Johns Hopkins University Dr. Slusher and Dr. Rais will assist Dr. Boateng with perform an in vivo rat brain and plasma pharmacokinetic analysis (one specie) for three compounds. $40,938
Rowan University The ultimate goal of these experiments is to identify new treatments for ADHD and substance use disorders. This study focuses on comprehensively evaluating lead… $101,624
University Of Florida Year 2 funding $95,758
University Of Florida Overall efforts on the modeling and computational design, including D4R subtype comparative dynamics simulation, agonists and antagonists design and… $92,356
Rowan University The ultimate goal of these experiments is to identify new treatments for ADHD and substance use disorders. This study focuses on comprehensively evaluating lead… $101,624
Show all 11

Quick answers

Who received award DP1DA058385?

DP1DA058385 was awarded to High Point University by National Institute on Drug Abuse (National Institutes of Health) on May 1, 2023.

How much is award DP1DA058385 worth?

$3,531,300 has been obligated on DP1DA058385.

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