title: SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C.
abstract: SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson's disease models, and a D1-D2 heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D1 and D2 receptors in both rat brain and heterologous systems expressing human D1 or D2 receptors. Contrary to common assumptions, SKF-83959 is similar to the classical, well-characterized partial agonist SKF38393 in all systems. It is a partial agonist (not an antagonist) at adenylate cyclase in vitro and ex vivo, and is a partial agonist in D1-mediated β-arrestin recruitment. Contrary to earlier reports, it does not have D1-mediated effects on PLC signaling in heterologous systems. Because drug metabolites can also contribute, its 3-N-demethylated analog also was synthesized and tested. As expected from the known structure-activity relationships of the benzazepines, this compound also had high affinity for the D1 receptor and somewhat higher intrinsic activity than the parent ligand, and also might contribute to in vivo effects of SKF-83959. Together, these data demonstrate that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral data can be explained solely by its partial D1 agonism in canonical signaling pathway(s). Mechanisms that have been proposed based on the purported signaling novelty of SKF-83959 at PLC should be reconsidered.
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17036, USA.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Division of Medicinal Chemistry, and Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7160, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kant
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17036, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Blake
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17036, USA.
authors.forename: Vishakantha
authors.initials: V
authors.lastname: Murthy
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17036, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Boyd
authors.affiliation: Department of Psychiatry, Division of Medicinal Chemistry, and Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7160, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Wyrick
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17036, USA; Department of Psychiatry, Division of Medicinal Chemistry, and Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7160, USA. Electronic address: rmailman@psu.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Mailman
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D015259:Dopamine Agents / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases
keywords: Adenylate cyclase; Dopamine D(1) receptor; Dopamine D(5) receptor; Functional selectivity; Ligand bias; Partial agonist; Phospholipase C; Rat striatum; SKF-83959