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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Gray DL,Allen JA,Mente S,O'Connor RE,DeMarco GJ,Efremov I,Tierney P,Volfson D,Davoren J,Guilmette E,Salafia M,Kozak R,Ehlers MD

doi

10.1038/s41467-017-02776-7

subject

Has Abstract

pub_date

2018-02-14 00:00:00

pages

674

issue

1

issn

2041-1723

pii

10.1038/s41467-017-02776-7

journal_volume

9

pub_type

杂志文章

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