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The dopamine D1 receptor (D1R) is prominently expressed in the striatum and cerebral cortex and is an attractive target for treating Parkinson's disease and cognitive impairment in schizophrenia. While newer, noncatechol D1R agonists such as tavapadon have shown promise in recent clinical trials, the therapeutic utility of earlier catechol agonists such as A77636 was hampered by tolerance development. The mechanism underlying tolerance induction was suggested to involve very slow A77636 dissociation from the D1R, promoting prominent arrestin recruitment and receptor internalization associated with delayed recycling to the cell surface. Here, we compared the signaling and binding kinetics of five D1R agonists─dopamine, dihydrexidine, apomorphine, A77636, and tavapadon─using two time-resolved assays of agonist-induced β-arrestin2 recruitment and G protein-coupled inward rectifier potassium (GIRK, also known as Kir3) channel activation, respectively. Additionally, D1R internalization was studied using cell-surface ELISA. Tavapadon and apomorphine did not induce significant D1R internalization, whereas pronounced internalization was observed with A77636, dopamine, and dihydrexidine. GIRK response deactivation time courses upon agonist washout were longer for A77636 and tavapadon compared to dopamine, dihydrexidine, and apomorphine. Similarly, in the β-arrestin2 assay, signal decay upon antagonist addition was slower for A77636 and tavapadon compared to the other three agonists. Tavapadon and apomorphine were partial agonists in both assays, whereas A77636 and dihydrexidine showed efficacies similar to dopamine. While our results do not provide evidence for a direct correlation between agonist dissociation and liability to tolerance induction, the possibility remains that certain combinations of agonist characteristics, such as high efficacy paired with slow dissociation, are associated with tolerance induction by D1R agonists.
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