Novel Therapeutic GPCRs for Psychiatric Disorders

Komatsu, Hidetoshi

doi:10.3390/ijms160614109

Cited by 60 publications

(44 citation statements)

References 69 publications

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“…Along with Drd2, we selected Gpr52, Gpr88, Gpr6, Adora2a and Rgs9 transcripts to study their enrichment in ribosome bound RNA from Drd2+ cells versus total mRNA from each region. GPCRs Gpr52, Gpr88, Gpr6, and Adora2a are the most enriched GPCR transcripts in STR (Komatsu H et al 2014) and are considered potential therapeutic targets for neuropsychiatric disorders (Komatsu H 2015). Rgs family protein 9 is a regulator of G protein signaling in part by stimulating the GTPase activity of the G protein α subunits.…”

Section: Discussionmentioning

confidence: 99%

High sensitivity mapping of cortical dopamine D2 receptor expressing neurons

Khlghatyan

Quintana

Parent

et al. 2018

Preprint

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Section: Discussionmentioning

confidence: 99%

High sensitivity mapping of cortical dopamine D2 receptor expressing neurons

Khlghatyan

Quintana

Parent

et al. 2018

Preprint

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“…G protein-coupled receptors (GPCRs) account for approximately 30% of all current drug targets (Overington et al 2006;Komatsu 2015). The dopamine receptors belong to monoamine GPCRs and they play a significant role in the pathophysiology and treatment of psychosis and movement disorders.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

et al. 2016

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The dopaminergic hypothesis of schizophrenia is the main concept explaining the direct reasons of schizophrenia and the effectiveness of current antipsychotics. All antipsychotics present on the market are potent dopamine D 2 receptor antagonists or partial agonists. In this work we investigate a series of dopamine D 2 receptor antagonists which do not fulfill the criteria of the classical pharmacophore model as they do not possess a protonatable nitrogen atom necessary to interact with the conserved Asp(3.32). Such compounds are interesting, inter alia, due to possible better pharmacokinetic profile when compared to basic, ionizable molecules. By means of homology modeling, molecular docking and molecular dynamics we determined that the compounds investigated interact with Asp(3.32) via their amide nitrogen atom. It was found that the studied compounds stabilize the receptor inactive conformation through the effect on the ionic lock, which is typical for GPCR antagonists. We constructed a CoMFA model for the studied compounds with the following statistics:63. The quality of the CoMFA model was confirmed by high value of R 2 of the test set, equal 0.96. The CoMFA model indicated two regions where bulky substituents are favored and two regions where bulky substituents are not beneficial. Two red contour regions near carbonyl groups were identified meaning that negative charge would be favored here. Furthermore, the S-oxide group is connected with blue contour region meaning that positive charge is favored in this position. These findings may be applied for further optimization of the studied compound series.

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“…Notably, GPCRs could modulate secretase activities via signal transductions or their interactions with secretase components [10–13]. GPCRs are abundantly expressed in CNS and function as the major therapeutic targets for many neurological disorders [14, 15]. Whether these GPCRs or their targeting medications could modulate γ-secretase activity or Aβ generation requires further investigation.…”

Section: Introductionmentioning

confidence: 99%

An Anti-Parkinson’s Disease Drug via Targeting Adenosine A2A Receptor Enhances Amyloid-β Generation and γ-Secretase Activity

Lü

Cui

et al. 2016

PLoS ONE

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γ-secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP) and determines the generation of Aβ which is associated with Alzheimer’s disease (AD). Here we identified that an anti-Parkinson’s disease drug, Istradefylline, could enhance Aβ generation in various cell lines and primary neuronal cells of APP/PS1 mouse. Moreover, the increased generation of Aβ42 was detected in the cortex of APP/PS1 mouse after chronic treatment with Istradefylline. Istradefylline promoted the activity of γ-secretase which could lead to increased Aβ production. These effects of Istradefylline were reduced by the knockdown of A2AR but independent of A2AR-mediated G protein- or β-arrestin-dependent signal pathway. We further observed that A2AR colocalized with γ-secretase in endosomes and physically interacted with the catalytic subunit presenilin-1 (PS1). Interestingly, Istradefylline attenuated the interaction in time- and dosage-dependent manners. Moreover the knockdown of A2AR which in theory would release PS1 potentiated both Aβ generation and γ-secretase activity. Thus, our study implies that the association of A2AR could modulate γ-secretase activity. Istradefylline enhance Aβ generation and γ-secretase activity possibly via modulating the interaction between A2AR and γ-secretase, which may bring some undesired effects in the central nervous system (CNS).

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Novel Therapeutic GPCRs for Psychiatric Disorders

Cited by 60 publications

References 69 publications

High sensitivity mapping of cortical dopamine D2 receptor expressing neurons

High sensitivity mapping of cortical dopamine D2 receptor expressing neurons

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

An Anti-Parkinson’s Disease Drug via Targeting Adenosine A2A Receptor Enhances Amyloid-β Generation and γ-Secretase Activity

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