SKF83959 is a partial agonist, not a functionally selective dopamine D1 receptor ligand as commonly believed

Abstract

Full dopamine D1 agonists have shown promise in treating several central nervous system disorders. D1‐mediated adenylate cyclase (AC) activation reflects canonical signaling, but some reports have suggested that some D1 ligands also signal via phospholipase C (PLC) activation. It has been proposed and accepted that SKF83959 is a functionally selective D1 agonist that has high intrinsic activity at D1‐mediated PLC activation, but antagonism of D1‐mediated AC activation. Because of anomalies in the pharmacological evidence, we rigorously characterized the pharmacology of SKF83959 in vitro. Contrary to what is commonly assumed, SKF83959 has partial agonist activity at AC activation similar to the prototypical D1 partial agonist, SKF38393. Both SKF83959 and SKF38393 also have partial agonist activity for D1‐mediated β‐arrestin recruitment. Most importantly, no activation of PLC activation was found for either SKF83959 or SKF38393 even at very high pharmacological concentrations (≤300 μM). Thus, these data clearly demonstrate that SKF83959 is a potent low intrinsic activity D1 agonist at AC and β‐arrestin recruitment (consistent with its affinity for the D1 receptor), yet fails to activate PLC. These data show that SKF83959 is not a functionally selective ligand, that its behavioral effects can be explained by known mechanisms, and that its use as a novel probe of D1 receptors is ill‐founded.