ArticleNeuropharmacology2014
SKF-83959 is not a highly-biased functionally selective D1 dopamine receptor ligand with activity at phospholipase C.
Article in Neuropharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Intracellular GPCR modulators enable precision pharmacology.npj drug discovery · 2025Review
- G Protein-Coupled Receptor Dimerization-What Next?International journal of molecular sciences · 2024Review
- Effects of DPTQ, a novel positive allosteric modulator of the dopamine D1 receptor, on spontaneous eye blink rate and spatial working memory in the nonhuman primate.Psychopharmacology · 2023Article
- Ligand recognition and biased agonism of the D1 dopamine receptor.Nature communications · 2022Article
- GPCR heteromers: An overview of their classification, function and physiological relevance.Frontiers in endocrinology · 2022Review
- Functional Selectivity of Dopamine DInternational journal of molecular sciences · 2021Review
- Article
- D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex.Molecular psychiatry · 2021Article
- Cancer and the Dopamine DThe Journal of pharmacology and experimental therapeutics · 2019Review
- A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods.Molecules (Basel, Switzerland) · 2019Article
- Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia.Biological psychiatry · 2017Review
- Evidence against dopamine D1/D2 receptor heteromers.Molecular psychiatry · 2015Article
- Evidence for limited D1 and D2 receptor coexpression and colocalization within the dorsal striatum of the neonatal mouse.The Journal of comparative neurology · 2015Article
- Identification of G protein-biased agonists that fail to recruit β-arrestin or promote internalization of the D1 dopamine receptor.ACS chemical neuroscience · 2015Article
- Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer.Neuroscience · 2015Article
- The dopamine D1-D2 receptor heteromer exerts a tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization.Pharmacology, biochemistry, and behavior · 2015Article
- Article
- Dopamine receptors - IUPHAR Review 13.British journal of pharmacology · 2015Review
- Dopamine D1 receptor signaling: does GαQ-phospholipase C actually play a role?The Journal of pharmacology and experimental therapeutics · 2014Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson's disease models, and a D1-D2 heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D1 and D2 receptors in both rat brain and heterologous systems expressing human D1 or D2 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 D1-mediated β-arrestin recruitment. Contrary to earlier reports, it does not have D1-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 D1 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 D1 ligand, and that its reported behavioral data can be explained solely by its partial D1 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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.