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

17 Citations (Scopus)

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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Arrestin
Dopamine D1 Receptors
dopamine
Catechols
Pharmacokinetics
Nervous System Diseases
Reward
Adenylyl Cyclases
Pharmaceutical Preparations
Cognition
Oral Administration
Parkinson Disease
Psychiatry
Rodentia
drugs
Chemical activation
Parkinson disease
Ligands
cognition
rodents

Cite this

Gray, D., Allen, J., Mente, S., O'Connor, R., Kozak, R., & Ehlers, M. (2018). Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor. Nature Communications, 9(674), [| DOI: 10.1038/s41467-017-02776-7].

Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor. / Gray, David; Allen, John; Mente, Scott; O'Connor, Rebecca; Kozak, Rouba; Ehlers, Michael.

In: Nature Communications, Vol. 9, No. 674, | DOI: 10.1038/s41467-017-02776-7, 14.02.2018.

Research output: Contribution to journalArticle

Gray, D, Allen, J, Mente, S, O'Connor, R, Kozak, R & Ehlers, M 2018, 'Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor', Nature Communications, vol. 9, no. 674, | DOI: 10.1038/s41467-017-02776-7.
Gray D, Allen J, Mente S, O'Connor R, Kozak R, Ehlers M. Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor. Nature Communications. 2018 Feb 14; 9(674). | DOI: 10.1038/s41467-017-02776-7.
Gray, David ; Allen, John ; Mente, Scott ; O'Connor, Rebecca ; Kozak, Rouba ; Ehlers, Michael. / Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor. In: Nature Communications. 2018 ; Vol. 9, No. 674.
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