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Identification of substituted benzazepines as functionally selective ligands of the D1


The D1 dopamine receptor has been implicated in numerous neuropsychiatric disorders, and various D1 ligands have shown great potential as therapeutic agents. However, numerous side effects have limited their clinical use. Additionally, it is unknown which D1-mediated signaling pathways are responsible for therapeutic effects versus side effects. Recently, compounds that modulate one signaling pathway while having no effect on other signaling pathways associated with the same receptor have been identified. These ‘”functionally selective” (FS) compounds present a novel way in which to target individual pathways while minimizing signaling through others. Previous studies have identified several substituted benzazepine compounds, including SKF83959, SKF38393, SKF82957, SKF77434, and SKF75670, as D1 agonists. However, the in vivo effects of these compounds have not correlated well to their in vitro pharmacological activities. This is especially true of SKF83959, which has been described as an “atypical” D1 agonist that does not induce the same behaviors in rodents as “typical” D1 agonists. In order to determine the functional effects of these compounds on numerous signaling pathways, a series of substituted benzazepines, as well as structurally dissimilar D1 agonists, were tested for their effects on D1-mediated cAMP accumulation and D1- mediated beta-arrestin recruitment, and using live cell functional assays. With respect to beta-arrestin recruitment, SKF83959, SKF38393, SKF82957, SKF77434, and SKF75670 were antagonists of this response whereas other substituted benzazepines were nearly full agonists, with efficacies ranging from 60-75%. In order to study the effects of these compounds on D1-mediated cAMP production, our study utilized the DiscoveRx (DRX) HitHunter assay, an antibody-based assay that provides a direct measurement of cAMP accumulation. In the DRX D1 cAMP assay, the compounds SKF83959, SKF38393, SKF82957, SKF77434, and SKF75670 showed partial agonism/full agonism, with efficacies ranging from 50-95% that of dopamine. In contrast, the structurally dissimilar D1 agonists and other substituted benzazepines exhibited full agonism (90-120% that of dopamine). These behaviors were confirmed when the five SKF compounds of interest exhibited partial antagonism in cAMP production, whereas all other compounds showed almost no antagonistic behavior. Thus, we have identified a group of substituted benzazepine ligands, SKF83959, SKF38393, SKF82957, SKF77434, and SKF75670, that are antagonists of D1 receptor-mediated recruitment of beta-arrestin and are agonists of G protein cAMP production. Taken together, these data suggest a group of substituted benzazepines that are functionally selective for the cAMP-mediated signaling pathway of the D1 receptor.

Last updated December 14, 2012