Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor

David Gray, John Allen, Scott Mente, Rebecca O'Connor, Rouba Kozak, Michael Ehlers

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for neurologic and psychiatric diseases due to the fundamental role of D1Rs in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive. Here we report a novel series of selective, potent non-catechol D1R agonists with promising in vivo pharmacokinetic properties. These ligands stimulate adenylyl cyclase signaling and are efficacious in a rodent model of Parkinson's disease after oral administration. They exhibit distinct binding to the D1R orthosteric site and a novel functional profile including minimal receptor desensitization, reduced recruitment of β-arrestin, and sustained in vivo efficacy. These results reveal a novel class of D1 agonists with favorable drug-like properties, and define the molecular basis for catechol-specific recruitment of β-arrestin to D1Rs.
Original languageEnglish (US)
Article number| DOI: 10.1038/s41467-017-02776-7
JournalNature Communications
Volume 9
Issue number674
StatePublished - Feb 14 2018

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