Synthesis and Pharmacological Evaluation of Noncatechol G Protein Biased and Unbiased Dopamine D1 Receptor Agonists

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 β-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 Gs-dependent cAMP signaling and β-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.