An investigation into ligand selectivity between dopamine receptor subtypes, biased agonism, and protean agonism
Publication Date
July 31, 2026
Creator
Kathryn R Wilson
Abstract
The G protein-coupled dopamine receptors D2R and D3R have long been considered major targets for antipsychotics in the treatment of disorders like schizophrenia. Typical, or first-generation antipsychotics tend to antagonise both dopamine and serotonin receptors in an effort to alleviate symptoms; the more modern atypical, or second-generation, antipsychotics (SGAs) display greater preference for antagonising serotonin receptors, and are termed ‘atypical’ due to their association with lower reported occurrences of extrapyramidal side effects. As these side effects are characterised by a loss of fine motor control and are thought to occur due to the mass blockade of D2Rs, these ligands’ higher relative selectivity for serotonin receptors is one potential explanation for their atypicality.
Recent findings suggest that one SGA, quetiapine, displayed biased agonism at the D3R, favouring recruitment of and signalling via β-arrestin 2-mediated pathways over the receptor’s associated G protein, resulting in modulation of calcium channels localised to the site of action potential initiation in prefrontal cortex pyramidal neurons. Further, said paper also demonstrated that treatment with quetiapine abolishes D3R function through postendocytic receptor degradation by G protein-coupled receptor-associated sorting protein 1 (GASP1). The authors propose this as a hitherto overlooked aspect of atypicality which, if accurate, could be important for future antipsychotic drug design and the potential for developing ligands which can reduce cell surface receptor populations as opposed to just antagonising them.
The aim of this research was to optimise assay methods to support the investigation of agonist action at both D2R and D3R with the overall purpose of verifying these claims of biased agonism.
In order to achieve this, multiple assays were attempted and optimised for the purpose of achieving consistency and repeatability of experiments measuring the activation of the G protein and the recruitment of β-arrestin 2. Attempts were made at reducing variability between repeats using a βγ-release assay, and later a TRUPATH assay, before settling on a mGo assay, which utilises a modified Gαo G protein subunit (or ‘miniG protein’), alongside a β-arrestin 2 assay, the optimisation of which were more successful.
Using these optimised assays, behaviours of various commonly prescribed SGAs were observed alongside a control dopamine receptor agonist, with particular focus on quetiapine’s action.
From this, it was possible to conclude that there is no evidence of quetiapine facilitating β-arrestin 2-mediated signalling at either the D2R or the D3R, potentially contradicting findings by Schamiloglu et al (2023) which suggested that quetiapine stimulates ERK phosphorylation in a β-arrestin 2-dependent manner at the D3R. Further, the recruitment of β-arrestin 2 to the D3R did not appear to correlate to observed receptor internalisation, even in the case of the control agonist quinpirole, though further research would be necessary to validate any absence of receptor internalisation and to understand the previous observations of the ERK1/2 signal stimulated by quetiapine through the D3R.
Item Type
ethesis
Thesis Type
MRes
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Subjects (LC)
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