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Defining Structure–Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists
journal contribution
posted on 2019-03-15, 00:00 authored by Michael
L. Martini, Jing Liu, Caroline Ray, Xufen Yu, Xi-Ping Huang, Aarti Urs, Nikhil Urs, John D. McCorvy, Marc G. Caron, Bryan L. Roth, Jian JinG protein-coupled receptors (GPCRs)
are capable of downstream signaling
through distinct noncanonical pathways such as β-arrestins in
addition to the canonical G protein-dependent pathways. GPCR ligands
that differentially activate the downstream signaling pathways are
termed functionally selective or biased ligands. A class of novel
non-catechol G protein-biased agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the
first comprehensive structure–functional selectivity relationship
study measuring GS and β-arrestin2 recruitment activities
focused on four regions of this scaffold, resulting in over 50 analogs
with diverse functional selectivity profiles. Some compounds became
potent full agonists of β-arrestin2 recruitment, while others
displayed enhanced GS bias compared to the starting compound.
Pharmacokinetic testing of an analog with an altered functional selectivity
profile demonstrated excellent blood–brain barrier penetration.
This study provides novel tools for studying ligand bias at D1R and paves the way for developing the next generation of
biased D1R ligands.
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GPCR ligandsD 1 R ligandsG Sdopamine D 1 receptorligand biasNon-Catechol Dopamine D 1 Receptor Agonists G protein-coupled receptorsSFSRG S biasselectivity profileD 1 Rβ- arrestinscanonical G protein-dependent pathwaysnovel toolscompoundnoncanonical pathways50 analogsPharmacokinetic testingnovel non-catechol G protein-biased agonistsβ- arrestin 2 recruitment activitiesβ- arrestin 2 recruitmentselectivity profiles
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