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SKF83959 is a partial agonist, not a functionally selective dopamine D 1 receptor ligand as commonly believed
Author(s) -
Lee SangMin,
Murthy Vishakantha,
Mailman Richard
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1171.5
Subject(s) - agonist , partial agonist , intrinsic activity , receptor , chemistry , endogenous agonist , ligand (biochemistry) , dopamine , pharmacology , microbiology and biotechnology , neuroscience , biology , biochemistry , dopamine receptor d1
Full dopamine D 1 agonists have shown promise in treating several central nervous system disorders. D 1 ‐mediated adenylate cyclase (AC) activation reflects canonical signaling, but some reports have suggested that some D 1 ligands also signal via phospholipase C (PLC) activation. It has been proposed and accepted that SKF83959 is a functionally selective D 1 agonist that has high intrinsic activity at D 1 ‐mediated PLC activation, but antagonism of D 1 ‐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 D 1 partial agonist, SKF38393. Both SKF83959 and SKF38393 also have partial agonist activity for D 1 ‐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 D 1 agonist at AC and β‐arrestin recruitment (consistent with its affinity for the D 1 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 D 1 receptors is ill‐founded.