Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 10, Issue 5, Pages 792-799Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00050
Keywords
dopamine 1 receptor; biased agonism; functional selectivity; noncatechol; cAMP; beta-arrestin
Categories
Funding
- National Institutes of Health [P50 DA033935, P30 DA028821, T32 DA07287]
- Pharmaceutical Research and Manufacturers of America Foundation (PhRMA Research Starter Grant ) [RSGPT18]
- Center for Addiction Research at the University of Texas Medical Branch
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Noncatechol heterocycles have recently been discovered as potent and selective G protein biased dopamine 1 receptor (D1R) agonists with superior pharmacokinetic properties. To determine the structure-activity relationships centered on G protein or beta-arrestin signaling bias, systematic medicinal chemistry was employed around three aromatic pharmacophores of the lead compound 5 (PF2334), generating a series of new molecules that were evaluated at both D1R G(s)-dependent cAMP signaling and beta-arrestin recruitment in HEK293 cells. Here, we report the chemical synthesis, pharmacological evaluation, and molecular docking studies leading to the identification of two novel noncatechol D1R agonists that are a subnanomolar potent unbiased ligand 19 (PW0441) and a nanomolar potent complete G protein biased ligand 24 (PW0464), respectively. These novel D1R agonists provide important tools to study D1R activation and signaling bias in both health and disease.
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