title: Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists.
abstract: Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first β-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.
authors: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors: Xin
authors: X
authors: Chen
authors: Maria F
authors: MF
authors: Sassano
authors: Lianyou
authors: L
authors: Zheng
authors: Vincent
authors: V
authors: Setola
authors: Meng
authors: M
authors: Chen
authors: Xu
authors: X
authors: Bai
authors: Stephen V
authors: SV
authors: Frye
authors: William C
authors: WC
authors: Wetsel
authors: Bryan L
authors: BL
authors: Roth
authors: Jian
authors: J
authors: Jin
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000068180:Aripiprazole; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010622:Phencyclidine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins
chemical_list: D014150:Antipsychotic Agents; D019390:Arrestins; D008024:Ligands; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins; D000068180:Aripiprazole; D000242:Cyclic AMP; D010622:Phencyclidine