Faculty Collaboration Database

Designing Functionally Selective Noncatechol Dopamine D₁ Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem Neurosci 2019 Sep 18;10(9):4160-4182

Date

08/08/2019

Pubmed ID

31387346

Pubmed Central ID

PMC6785188

DOI

10.1021/acschemneuro.9b00410

Scopus ID

2-s2.0-85071950767 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportunities for treating Parkinson's Disease (PD) motor and cognitive deficits. Biased D₁ dopamine ligands that differentially activate G protein over β-arrestin recruitment pathways are valuable chemical tools for dissecting positive versus negative effects in drugs for PD. Here, we reveal an iterative approach toward modification of a D₁-selective noncatechol scaffold critical for G protein-biased agonism. This approach provided enhanced understanding of the structural components critical for activity and signaling bias and led to the discovery of several novel compounds with useful pharmacological properties, including three highly G_S-biased partial agonists. Administration of a potent, balanced, and brain-penetrant lead compound from this series results in robust antiparkinsonian effects in a rodent model of PD. This study suggests that the noncatechol ligands developed through this approach are valuable tools for probing D₁ receptor signaling biology and biased agonism in models of neurologic disease.

Author List

Martini ML, Ray C, Yu X, Liu J, Pogorelov VM, Wetsel WC, Huang XP, McCorvy JD, Caron MG, Jin J

Author

John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antiparkinson Agents
Arrestins
Cyclic AMP
Dopamine
Dopamine Agonists
Receptors, Dopamine D1
Receptors, Dopamine D2
Receptors, G-Protein-Coupled