Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants

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PROJECT SUMMARY/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 α2A adrenergic receptors (α2ARs), 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 α2AR, and differential signaling at Gαi1 versus Gαo1. 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.