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Identification of substituted benzazepines as functionally selective ligands of the D 1 dopamine receptor
Author(s) -
Conroy Jennie Lynn,
Doyle Trevor B,
Sibley David R
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.655.3
Subject(s) - benzazepines , agonist , internalization , dopamine , receptor , partial agonist , chemistry , pharmacology , functional selectivity , intrinsic activity , g protein coupled receptor , dopamine receptor , dopamine agonist , neuroscience , biology , biochemistry , stereochemistry
The D 1 dopamine receptor has been implicated in numerous neuropsychiatric disorders, and various D 1 ‐selective ligands have shown potential as therapeutic agents. Functionally‐selective, or signaling biased compounds present a unique therapeutic opportunity to target individual pathways while minimizing signaling through others. A series of “atypical” substituted benzazepines, and D 1 “typical” agonists, were tested for their functional effects on D 1 ‐mediated cAMP accumulation, D 1 ‐mediated β‐arrestin recruitment, and D 1 receptor internalization using live cell functional assays. With respect to β‐arrestin recruitment, some “atypical” benzazepines were found have no agonist efficacy at this response, but instead functioned as antagonists. Other “typical” agonists exhibited a range of efficacies from 20–110%. As with β‐arrestin recruitment, the “atypical” benzazepine agonists exhibited little agonist efficacy in an assay of receptor internalization, yet other “typical” compounds were full agonists. Using two distinct cAMP accumulation assays, “typical” agonists were found to elicit increases in D 1 cAMP accumulation similar to that produced by dopamine, while the “atypical” agonists were found to be partial‐full agonists. Taken together, these experiments identify a novel series of substituted benzazepines that are G protein‐biased or functionally‐selective agonists of the D 1 receptor.