Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists

Chen, Xin; McCorvy, John D.; G., Fischer, Matthew; Butler, Kyle V.; Shen, Yudao; Roth, Bryan L.; Jin, Jian

doi:10.1021/acs.jmedchem.6b01208

Cited by 46 publications

(66 citation statements)

References 52 publications

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“…functionally selective agonists. Biased agonism, has been identified for many therapeutically important GPCRs such as α 1 -and β-adrenergic receptors [16,[23][24][25], μ-opioid receptors (MOR) [26,27], cannabinoid receptors [28,29], D 2L and D 1 dopamine receptors [30][31][32][33], serotonin receptors [17,34,35], chemokine receptor CCR7 [36,37], gonadotropin-releasing hormone receptors [38,39], parathyroid hormone 1 receptors (PTH1R) [40,41], angiotensin 1A (AT 1A ) receptors [42] or MC4 melanocortin receptors [43].…”

Section: Przykłady Selektywności Funkcjonalnejmentioning

confidence: 99%

“…Liczne badania sugerują, że selektywność funkcjonalna wobec receptora dopaminowego D 2 może stanowić podstawę pożądanego profilu działania leków przeciwpsychotycznych [30,31,48,49]. Ich wyniki bywają jednak rozbieżne.…”

Section: Przykłady Selektywności Funkcjonalnejunclassified

“…Numerous studies have suggested that functional selectivity towards dopamine D 2 receptor could be the basis for the desired profile of antipsychotic effect [30,31,48,49]. However, their results are sometimes divergent.…”

Section: Rola Receptorów 5-ht 1a Jako Celów Terapeutycznychmentioning

confidence: 99%

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Functional selectivity – chance for better and safer drugs?

Śniecikowska¹,

Głuch‐Lutwin²,

Bucki³

et al. 2017

ppn

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Purpose: The article reviews the current state of knowledge about functional selectivity (biased agonism) at G protein-coupled receptors (GPCRs), with a particular focus on serotonin 5-HT 1A receptors. Views: Recently, functional selectivity has been one of the fastest growing topics in GPCRs pharmacology. Research on this phenomenon allowed identification of signal transduction pathways which can be preferentially targeted to achieve improved therapeutic effects or, conversely, which are associated with adverse effects. Oliceridine, a phase III clinical candidate for treatment of pain, is an example of a functionally selective ligand of µ-opioid receptors that preferentially activates signal transduction via G proteins rather than β-arrestin. Biased agonism, or the ability to preferentially activate specific signalling pathways, has been identified for many therapeutically important GPCRs, such as µ-opioid receptors, α 1 -and β 2 -adrenoceptors, dopamine D 2L and D 1 receptors, angiotensin 1A receptor, as well as 5-HT 2 and 5-HT 1A serotonin receptors. The recently discovered compounds F15599 and F13714 have been identified as functionally and regionally selective ligands of 5-HT 1A receptors. These compounds constitute a new generation of pharmacological tools with high therapeutic potential, which is currently being investigated for the treatment of disorders including Parkinson's disease, depression and Rett syndrome. Conclusions: Functional selectivity (biased agonism) enables separation of the therapeutic effect from the adverse effects, so far considered to be intrinsically linked to the mechanism of action, by preferentially targeting signal transduction pathways associated with beneficial effects. It may therefore offer new opportunities for improved development of more effective and safer drugs. Key words: functional selectivity, biased agonism, 5-HT 1A receptor, F15599, F13714. StreszczenieCel: W pracy przedstawiono aktualny stan wiedzy na temat zjawiska selektywności funkcjonalnej (stronniczego agonizmu) w farmakologii receptorów sprzężonych z białkiem G (G protein-coupled receptors -GPCRs), ze szczególnym uwzględnieniem receptorów serotoninowych typu 1A. Poglądy: W ostatnich latach selektywność funkcjonalna stała się jednym z najszybciej rozwijających się tematów w farmakologii GPCRs. Badania nad tym zjawiskiem umożliwiają identyfikację szlaków transdukcji sygnału, które są preferowane dla efektu terapeutycznego lub związane z efektami niepożądanymi danego receptora. Przykładem może być olicerydyna, agonista receptorów opioidowych, selektywny funkcjonalnie wobec ścieżki przekazywania sygnału przez białko G względem β-arestyny, tj. nowy kandydat na lek przeciwbólowy. Selektywność funkcjonalna, nazywana inaczej stronniczym agonizmem, czyli zdolność do preferencyjnej aktywacji wybranej ścieżki sygnałowej, została zidentyfikowana w obrębie całej gamy ważnych terapeutycznie celów z rodziny GPCRs, m.in. receptorów μ-opioidowych, α 1 -i β 2 -adrenergicznych, dopaminowych D 2L i D 1 , angiotensynowy...

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Section: Przykłady Selektywności Funkcjonalnejmentioning

confidence: 99%

Section: Przykłady Selektywności Funkcjonalnejunclassified

See 1 more Smart Citation

Functional selectivity – chance for better and safer drugs?

Śniecikowska¹,

Głuch‐Lutwin²,

Bucki³

et al. 2017

ppn

View full text Add to dashboard Cite

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“…Therefore, the involvement of DRs in the modulation of PD has led medicinal chemists to invest on the research of DR agonists with higher subtype selectivity. Until recently, several classes of small molecules targeting D2R and D3R receptors have been discovered [55][56][57][58][59][60][61][62][63][64][65][66][67]. According to their chemical scaffolds, these DR agonists have been classified into two major classes (see Fig.…”

Section: Dopamine Receptorsmentioning

confidence: 99%

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

et al. 2017

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Parkinson's Disease (PD) is a long-term neurodegenative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated to long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated to dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused in a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure-and ligand-based in silico approaches for the development of small molecules to target these receptors.

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“…Differences in assay timing might contribute to discrepancies of bias estimates reported in the literature. For example, aripiprazole has been reported to be an arrestin-biased ligand but the efficacy varies from 10 to 100% and the time point from 5 minutes to 20 hours [13][14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

A new kinetic method for measuring agonist efficacy and ligand bias using high resolution biosensors and a kinetic data analysis framework

Hoare¹,

Tewson

Quinn

et al. 2019

Preprint

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The kinetics/dynamics of signaling are of increasing value for G-protein-coupled receptor therapeutic development, including spatiotemporal signaling and the kinetic context of biased agonism. Effective application of signaling kinetics to developing new therapeutics requires reliable kinetic assays and an analysis framework to extract kinetic pharmacological parameters. Here we describe a platform for measuring arrestin recruitment kinetics to GPCRs using a high quantum yield, genetically encoded fluorescent biosensor, and a new analysis framework to quantify the recruitment kinetics. The sensor enabled high temporal resolution measurement of arrestin recruitment to the angiotensin AT1 and vasopressin V2 receptors. The analysis quantified the initial rate of arrestin signaling (kτ), a biologicallymeaningful kinetic drug efficacy parameter, by fitting time course data using routine curve-fitting methods. Biased agonism was assessed by comparing kτ values for arrestin recruitment with those for Gq signaling via the AT1 receptor. The kτ ratio values were in good agreement with bias estimates from existing methods. This platform potentially improves and simplifies assessment of biased agonism because the same assay modality is used to compare pathways (potentially in the same cells), the analysis method is parsimonious and intuitive, and kinetic context is factored into the bias measurement. Receptor excess over arrestin

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Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists

Cited by 46 publications

References 52 publications

Functional selectivity – chance for better and safer drugs?

Functional selectivity – chance for better and safer drugs?

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

A new kinetic method for measuring agonist efficacy and ligand bias using high resolution biosensors and a kinetic data analysis framework

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