Characterization of a Novel Binding Site for a Positive Allosteric Modulator of the D1 Dopamine Receptor

Authors

• ST Dimova
• JN Hanson
• AN Nilson
• F Wang
• J Rayadurgam
• A Goldberg
• KD Luderman
• L Shi
• KJ Frankowski
• DR Sibley

Abstract

Dopamine (DA) is an important neurotransmitter involved in regulating numerous physiological functions including movement, cognition, and reward pathways, among others. As such, it is involved in a plethora of neurological disorders including Parkinson’s Disease (PD). Current treatments of PD aim to improve dopamine signaling, leading to the reduction of motor symptoms. Specifically targeting the D1 DA receptor (D1R) could improve motor and cognitive symptoms of PD. However, these D1R agonists have largely failed due to rapid metabolism and poor bioavailability. Due to these pharmacokinetic liabilities, other pharmacological approaches are being taken to treat PD. This project explores the use of positive allosteric modulators (PAMs) as an alternative treatment option that can overcome the pitfalls of D1R agonists. Our lab previously identified and characterized a novel small molecule that elicits PAM activity at the D1R, known as MLS6585. This compound increased the potency and efficacy of dopamine in cAMP and beta-arrestin recruitment assays. To optimize and improve the potency of the PAM, we made over 100 analogs of MLS6585, and from these identified two analogs with improved PAM activity, UNC10062 and UNC9815. Additionally, our lab utilized mutants of the D1R to elucidate the allosteric binding pocket on the receptor. Modeling and mutant data suggested the compound binds in the TM1, TM7, and helix 8 interface. Utilizing cluster and point residue mutations, we explored the role of these regions on PAM functional activity. Fully delineating this allosteric binding pocket will aid in the synthesis of more efficacious PAMs using structure-guided analog design.

Scientific Focus Area: Molecular Pharmacology

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