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Impaired ?-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 ?-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 ?-arrestin to D1Rs.

SUBMITTER: Gray DL 

PROVIDER: S-EPMC5813016 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Gray David L DL   Allen John A JA   Mente Scot S   O'Connor Rebecca E RE   DeMarco George J GJ   Efremov Ivan I   Tierney Patrick P   Volfson Dmitri D   Davoren Jennifer J   Guilmette Edward E   Salafia Michelle M   Kozak Rouba R   Ehlers Michael D MD  

Nature communications 20180214 1


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  ...[more]

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