SKF-83959 is not a highly-biased functionally selective D₁ dopamine receptor ligand with activity at phospholipase C

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 D ₁ 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.