Details

Autor(en) / Beteiligte

• Lee, Sang-Min
• Kant, Andrew
• Blake, Daniel
• Murthy, Vishakantha
• Boyd, Kevin
• Wyrick, Steven J
• Mailman, Richard B

Titel

SKF-83959 is not a highly-biased functionally selective D sub(1) dopamine receptor ligand with activity at phospholipase C

Ist Teil von

• Neuropharmacology, 2014-11, Vol.86, p.145-154

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrah y dro-1H-3-benzazepine] is reported to be a functionally selective dopamine D sub(1) receptor ligand with high bias for D sub(1)-mediated phospholipase C (PLC) versus D sub(1)-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson's disease models, and a D sub(1)-D sub(2) heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D sub(1) and D sub(2) receptors in both rat brain and heterologous systems expressing human D sub(1) or D sub(2) 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 D sub(1)-mediated beta -arrestin recruitment. Contrary to earlier reports, it does not have D sub(1)-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 D sub(1) 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 D sub(1) ligand, and that its reported behavioral data can be explained solely by its partial D sub(1) 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.