Design of novel dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations

Zhang, Cuihua; Li, Qunlin; Meng, Lingwei; Ren, Yujie

doi:10.1080/07391102.2019.1590244

Cited by 25 publications

(15 citation statements)

References 59 publications

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“…D2-like receptors (D2/D3) are the main targets of antipsychotics ( Zhang et al., 2020 ). The D2 receptor is present in two isoforms D2S and D2L which differ because of a 29 AA insertion in the third intracellular loop on D2L ( Zuk et al., 2020 ).…”

Section: Section 1: Dopamine Receptorsmentioning

confidence: 99%

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Martel¹,

McArthur²

2020

Front. Pharmacol.

177

125

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Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cognition. The identification of five genes coding for different dopamine receptor subtypes, pharmacologically grouped as D1- (D1 and D5) or D2-like (D2S, D2L, D3, and D4) has allowed the demonstration of differential receptor function in specific neurocircuits. Recent observation on dopamine receptor signaling point at dopamine—glutamate-NMDA neurobiology as the most relevant in schizophrenia and for the development of new therapies. Progress in the chemistry of D1- and D2-like receptor ligands (agonists, antagonists, and partial agonists) has provided more selective compounds possibly able to target the dopamine receptors homo and heterodimers and address different schizophrenia symptoms. Moreover, an extensive evaluation of the functional effect of these agents on dopamine receptor coupling and intracellular signaling highlights important differences that could also result in highly differentiated clinical pharmacology. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine – glutamate NMDA systems interactions.

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Section: Section 1: Dopamine Receptorsmentioning

confidence: 99%

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Martel¹,

McArthur²

2020

Front. Pharmacol.

177

125

View full text Add to dashboard Cite

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“…Furthermore, 1-3 displayed additional H-bond interactions with serine residues (Ser107, Ser188, and Ser198) and aspartic acid residues (Asp314 and Asp187). Similarly, at D 2 R, 1-3 interacted with the key interacting residues Asp114, Trp100, and Phe389 [42]. All three ligands bound to D 2L R with high affinity and the binding energy was lower than that of the reference antagonist butaclamol.…”

Section: Discussionmentioning

confidence: 96%

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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“…However, not 5-HT 2A receptor antagonism per se but a combined blockage of D2 and 5-HT 2A receptors is believed to confer the efficacy of a second-generation antipsychotics [ 151 , 152 ]. Indeed, the atypical antipsychotics are frequently characterized by their combined action for the antagonism of 5-HT 2A and D2 receptors [ 153 ]. Studies have shown that this treatment strategy can efficiently reduce the negative and cognitive symptoms as well as minimize the side effects [ 154 ].…”

Section: Serotonergic Receptorsmentioning

confidence: 99%

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

Boczek

Mackiewicz

Sobolczyk

et al. 2021

Cells

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Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through several downstream pathways, many of them engaging intracellular Ca2+ mobilization. Dysfunctions of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related regions are likely to underly the complex picture that includes the whole spectrum of positive and negative schizophrenia symptoms. Therefore, the progress in our understanding of GPCRs function in the control of brain cognitive functions is expected to open new avenues for selective drug development. In this paper, we review and synthesize the recent data regarding the contribution of neurotransmitter-GPCRs signaling to schizophrenia symptomology.

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Design of novel dopamine D₂ and serotonin 5-HT_2A receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations

Cited by 25 publications

References 59 publications

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

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

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

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Design of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations

Cited by 25 publications

References 59 publications

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

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

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

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Design of novel dopamine D₂ and serotonin 5-HT_2A receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations