Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment

Jůza, Radomír; Vojtěchová, Iveta; Stefkova-Mazochova, Kristyna; Dehaen, Wim; Petrásek, Tomáš; Prchal, Lukáš; Kobrlová, Tereza; Janoušek, Jiří; Vlček, Přemysl; Mezeiová, Eva; Svozil, Daniel; Karasová, Jana Žďárová; Pejchal, Jaroslav; Stark, Holger; Satała, Grzegorz; Bojarski, Andrzej J.; Kubacka, Monika; Mogilski, Szczepan; Randáková, Alena; Musílek, Kamil; Soukup, Ondřej; Korábečný, Jan

doi:10.1016/j.ejmech.2022.114193

Cited by 6 publications

(5 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The desirability BBB score for CNS drugs ranges from 4 to 6, while for non-CNS drugs it goes from 0 to 3. The algorithm was chosen as it has high predictive value as confirmed in the in vitro – in vivo correlation studies. , Consequently, we compared the BBB score of the best hits generated until the molecular docking protocol with all 21 SIs of aldose reductase protein. Out of these 21 compounds, four of them were proposed as potential inhibitors in the literature.…”

Section: Methodsmentioning

confidence: 99%

“…The algorithm was chosen as it has high predictive value as confirmed in the in vitro−in vivo correlation studies. 46,47 molecular bioactivity by a single or ensemble of ML/DL models in which atomic weight equals the difference in predicted probabilities before and after the bits are removed. 48 The analysis of similarity maps highlighting the green color atoms signifies the presence of important fragments which contribute to the bioactivity, while the pink color atoms indicate the dissimilar property with another compound; this analogy can help in optimizing the tested compounds by modifying their key fragments, which can further help in gaining better experimental activity.…”

Section: = + Binary Accuracy (Bac)mentioning

confidence: 99%

See 1 more Smart Citation

Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening

Kashyap,

Mahapatra,

Ahmed

et al. 2023

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Aldose reductase (ALR2) is a notable enzyme of the polyol pathway responsible for aggravating diabetic neuropathy complications. The first step begins when it catalyzes the reduction of glucose to sorbitol with NADPH as a coenzyme. Elevated concentrations of sorbitol damage the tissues, leading to complications like neuropathy. Though considerable effort has been pushed toward the successful discovery of potent inhibitors, its discovery still remains an elusive task. To this end, we present a 3D convolutional neural network (3D-CNN) based ALR2 inhibitor classification technique by dealing with snapshots of images captured from 3D chemical structures with multiple rotations as input data. The CNN-based architecture was trained on the 360 sets of image data along each axis and further prediction on the Maybridge library by each of the models. Subjecting the retrieved hits to molecular docking leads to the identification of the top 10 molecules with high binding affinity. The hits displayed a better blood− brain barrier penetration (BBB) score (90% with more than four scores) as compared to standard inhibitors (38%), reflecting the superior BBB penetrating efficiency of the hits. Followed by molecular docking, the biological evaluation spotlighted five compounds as promising ALR2 inhibitors and can be considered as a likely prospect for further structural optimization with medicinal chemistry efforts to improve their inhibition efficacy and consolidate them as new ALR2 antagonists in the future. In addition, the study also demonstrated the usefulness of scaffold analysis of the molecules as a method for investigating the significance of structurally diverse compounds in data-driven studies. For reproducibility and accessibility purposes, all of the source codes used in our study are publicly available.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: = + Binary Accuracy (Bac)mentioning

confidence: 99%

Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening

Kashyap,

Mahapatra,

Ahmed

et al. 2023

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…We will use the algorithm invented by Gupta et al 552 to calculate so‐called BBB score for selected D 2 R modulators to predict whether these derivatives can permeate through the BBB. This algorithm was chosen because it has a high predictive value confirmed in several in vivo studies 565,566 . According to this algorithm, if the ligand has a BBB score ranging between 4 and 5, it has a 54.5% probability of crossing the BBB.…”

Section: Medicinal Chemistry Partmentioning

confidence: 99%

“…This algorithm was chosen because it has a high predictive value confirmed in several in vivo studies. 565,566 According to this algorithm, if the ligand has a BBB score ranging between 4 and 5, it has a 54.5% probability of crossing the BBB. The score between 5 and 6 resulted a 90.3% probability.…”

Section: Multitargets Drugsmentioning

confidence: 99%

Recent advances in dopamine D₂ receptor ligands in the treatment of neuropsychiatric disorders

Jůza

Musílek

Mezeiová

et al. 2022

Medicinal Research Reviews

Self Cite

View full text Add to dashboard Cite

Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D 1-5 Rs), which belong to the G protein-coupled receptor family. Antagonists and partial agonists of D 2 Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D 2 R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4-(2,3-dichlorophenyl), 4-(2-methoxyphenyl)-, 4-(benzo[b]thiophen-4-yl)-1-substituted piperazine, and 4-(6fluorobenzo[d]isoxazol-3-yl)piperidine moieties are critical for high D 2 R affinity. Four to six atoms chains are optimal for D 2 R affinity with 4-butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D 2 R affinity. In this review, we provide a thorough overview of the therapeutic potential of D 2 R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D 2 R ligands, which have been developed in the last decade (2010-2021), and belong to the 1,4-disubstituted aromatic cyclic amine group. Due to the abundance of data,

show abstract

“…The dopamine receptor is the crucial target of all existing antipsychotics. Dopamine D 2 receptor antagonists are thought to control positive symptoms in patients with schizophrenia ( Farde et al, 1988 ; Casey and Canal, 2017 ; Juza et al, 2022 ). Schizophrenia may be controlled by the antagonism of the 5-HT 2A receptor in synergy with the antagonism of the dopamine D 2 receptor ( Andree et al, 1997 ).…”

Section: Introductionmentioning

confidence: 99%

Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia

Feng,

Hu,

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia.Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical.Results:In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094.Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.

show abstract

Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment

Cited by 6 publications

References 87 publications

Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening

Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening

Recent advances in dopamine D₂ receptor ligands in the treatment of neuropsychiatric disorders

Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia

Contact Info

Product

Resources

About

Novel D2/5-HT receptor modulators related to cariprazine with potential implication to schizophrenia treatment

Cited by 6 publications

References 87 publications

Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening

Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening

Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders

Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia

Contact Info

Product

Resources

About

Recent advances in dopamine D₂ receptor ligands in the treatment of neuropsychiatric disorders