G protein‐coupled receptor pharmacology—The next generation

Bräuner‐Osborne, Hans; Gether, Ulrik; Gloriam, David E.

doi:10.1111/bcpt.13291

Cited by 2 publications

(3 citation statements)

References 19 publications

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“…Their dysfunction is involved in many diseases and they are already used as therapeutic targets by 34% of drugs approved by the Food and Drug Administration (FDA). 7 GPR55 is a member of the GPCRs family that has been found to regulate inflammatory response, and innate and adaptive immune systems. 8 Wlodarczyk et al 9 reported that GPR55 expression in inflamed tissues is statistically significantly higher in Crohn's disease patients compared to ulcerative colitis patients.…”

Section: Introductionmentioning

confidence: 99%

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Antagonism of G protein-coupled receptor 55 prevents lipopolysaccharide-induced damages in human dental pulp cells

Shen

2022

Hum Exp Toxicol

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Pulpitis is a common oral inflammatory disease in dental pulp commonly associated with bacterial infection. G protein-coupled receptor 55 (GPR55) is a member of the G protein‐coupled receptors family that has been found to regulate inflammatory response. However, its roles in dental pulp inflammation have not been investigated. In this study, we used lipopolysaccharide (LPS) to induce inflammation in human dental pulp cells (hDPCs) to simulate an in vitro model of pulpitis. We found that LPS markedly induced the GPR55 expression in hDPCs. Treatment with the GPR55 antagonist ML-193 ameliorated the LPS-caused decrease in cell viability and increase in lactate dehydrogenase release. The upregulated inflammatory cytokines, interleukin-6 (IL-6) and tumour necrosis factor α, in LPS-challenged hDPCs were also attenuated by ML-193. Treatment with ML-193 ameliorated LPS-induced production of the inflammatory mediators cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2), and inducible nitric oxide synthase/nitric oxide (iNOS/NO) in hDPCs. ML-193 also inhibited the activation of Toll-like receptor 4-myeloid differentiation primary response 88-nuclear factor-κB (TLR4-Myd88-NF-κB) signaling in LPS-induced hDPCs via decreased expressions of TLR4, Myd88, and p-NF-κB 65. Our study provides evidence that the GPR55 antagonist ML-193 exhibited anti-inflammatory activity in LPS-stimulated hDPCs through inhibiting TLR4-Myd88-NF-κB signaling. The results imply that ML-193 might be a novel agent for pulpitis.

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Section: Introductionmentioning

confidence: 99%

“…Their dysfunction is involved in many diseases and they are already used as therapeutic targets by 34% of drugs approved by the Food and Drug Administration (FDA). 7…”

Section: Introductionmentioning

confidence: 99%

Antagonism of G protein-coupled receptor 55 prevents lipopolysaccharide-induced damages in human dental pulp cells

Shen

2022

Hum Exp Toxicol

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“…At present, 34% of FDA-approved drugs target GPCRs [10]. GPCRs are widely expressed and activated by a broad range of ligands, including neurotransmitters, hormones, and ions, as well as sensory signals [11]. Neurotransmitters bind to their specific receptors at the postsynaptic cleft and trigger or inhibit neuronal functions and signals by regulating the activity of ion channels.…”

Section: Introductionmentioning

confidence: 99%

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

Paudel

Park

Seong

et al. 2019

IJMS

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In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their role in Parkinson’s disease (PD) and depression, focusing on their ability to modulate dopaminergic receptors (D1R, D2LR, D3R, and D4R). In hMAO-A inhibition, 1–3 showed mild effects (50% inhibitory concentration (IC50): 54‒114 μM). However, 1 displayed moderate inhibition of the hMAO-B isozyme (IC50: 18.14 ± 1.06 μM) followed by mild inhibition by 2 (IC50: 57.71 ± 2.12 μM) and 3 (IC50: 90.59 ± 1.72 μM). Our kinetic study characterized the inhibition mode, and the in silico docking predicted that the moderate inhibitor 1 would have the lowest binding energy. Similarly, cell-based G protein-coupled receptors (GPCR) functional assays in vector-transfected cells expressing dopamine (DA) receptors characterized 1–3 as D1R/D2LR antagonists and D3R/D4R agonists. The half-maximum effective concentration (EC50) of 1–3 on DA D3R/D4R was 15.13/17.19, 20.18/21.05, and 12.63/‒ µM, respectively. Similarly, 1–3 inhibited 50% of the DA response on D1R/D2LR by 6.13/2.41, 16.48/31.22, and 7.16/18.42 µM, respectively. A computational study revealed low binding energy for the test ligands. Interactions with residues Asp110, Val111, Tyr365, and Phe345 at the D3R receptor and Asp115 and His414 at the D4R receptor explain the high agonist effect. Likewise, Asp187 at D1R and Asp114 at D2LR play a crucial role in the antagonist effects of the ligand binding. Our overall results depict 1–3 from M. alba root bark as good inhibitors of hMAO and potent modulators of DA function as D1R/D2LR antagonists and D3R/D4R agonists. These active constituents in M. alba deserve in-depth study for their potential to manage neurodegenerative disorders (NDs), particularly PD and psychosis.

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G protein‐coupled receptor pharmacology—The next generation

Cited by 2 publications

References 19 publications

Antagonism of G protein-coupled receptor 55 prevents lipopolysaccharide-induced damages in human dental pulp cells

Antagonism of G protein-coupled receptor 55 prevents lipopolysaccharide-induced damages in human dental pulp cells

Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

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