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

David L. Gray (), John A. Allen, Scot Mente, Rebecca E. O’Connor, George J. DeMarco, Ivan Efremov, Patrick Tierney, Dmitri Volfson, Jennifer Davoren, Edward Guilmette, Michelle Salafia, Rouba Kozak and Michael D. Ehlers ()
Additional contact information
David L. Gray: Pfizer Worldwide Research & Development
John A. Allen: Pfizer Worldwide Research & Development
Scot Mente: Pfizer Worldwide Research & Development
Rebecca E. O’Connor: Pfizer Worldwide Research & Development
George J. DeMarco: Pfizer Worldwide Research & Development
Ivan Efremov: Pfizer Worldwide Research & Development
Patrick Tierney: Pfizer Worldwide Research & Development
Dmitri Volfson: Pfizer Worldwide Research & Development
Jennifer Davoren: Pfizer Worldwide Research & Development
Edward Guilmette: Pfizer Worldwide Research & Development
Michelle Salafia: Pfizer Worldwide Research & Development
Rouba Kozak: Pfizer Worldwide Research & Development
Michael D. Ehlers: Pfizer Worldwide Research & Development

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02776-7

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