Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)

Bucki, Adam; Marcinkowska, Monika; Śniecikowska, Joanna; Zagórska, Agnieszka; Jamrozik, Marek; Pawłowski, Maciej; Głuch‐Lutwin, Monika; Siwek, Agata; Jakubczyk, Magdalena; Pytka, Karolina; Jastrzębska-Więsek, Magdalena; Partyka, Anna; Wesołowska, Anna; Mierzejewski, Paweł; Kołaczkowski, Marcin

doi:10.1016/j.ejmech.2020.112149

Cited by 9 publications

(19 citation statements)

References 40 publications

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“…Serotonin and its receptors, particularly the HTR2A, play roles in cognitive behaviors and psychiatric conditions such as depression, schizophrenia, and AD [4]. A multitarget-directed ligand, acting on HTR2A and DRD2, has been shown to exert an anti-aggressive and antipsychotic activity and is, therefore, a promising therapeutic option for BPSD [15]. In our study, herbs active ingredients were docked with DRD2 and HTR2A.…”

Section: Resultsmentioning

confidence: 83%

“…In this network, the red rectangular nodes represent the key protein targets of the herbs. The targets for Scutellariae radix were the highest (24), followed by Phellodendri chinrnsis cortex (15). We used the GO biological process analysis to further study the herbs' key protein targets.…”

Section: Resultsmentioning

confidence: 99%

“…It has been documented that serotoninergic, dopaminergic, and cholinergic systems are involved in BPSD pathogenesis, and the roles of HTR2A and DRD2 as therapeutic targets are evident [15]. We used molecular docking to determine the potential active ingredients that exhibited good binding activities to DRD2 and HTR2A.…”

Section: Discussionmentioning

confidence: 99%

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Novel Combination of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Wang

Shi

2021

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Alzheimer's disease (AD) is characterized by progressive cognitive decline. Besides cognitive deficit, AD is also characterized by behavioral and psychological symptoms in dementia (BPSD). However, therapeutic management of BPSD remains challenging. HuanglianJiedu decoction (HLJDD), a traditional Chinese prescription, consisting of four herbs, is applied to treat AD, especially AD with BPSD. Though HLJDD, has the traditional combination with the principal herb Coptidis rhizoma (Huang-lian), it might, however, not be suitable for treating BPSD. Elucidating the mechanism underlying each herb is critical to the disease-matched combination of HLJDD. In this study, network pharmacology was used to determine the targets and biological processes regulated by HLJDD in the treatment of BPSD. Moreover, molecular docking was utilized to evaluate the binding activity between the herbs' main active ingredients and neurotransmitter receptors. The results showed that Scutellariae radix (Huang-qin) and Phellodendri chinrnsis cortex (Huang-bai) exhibited better anti-BPSD effects when compared to Coptidis rhizoma and Gardeniae fructus (Zhi-zi). Scutellariae radix exhibited superior anti-neuroinflammation functions, with better blood vessel regulation effects. Phellodendri chinrnsis cortex showed a higher binding affinity to the dopamine D2 receptor (DRD2) and 5-hydroxytryptamine receptor 2A (HTR2A). Coptidis rhizoma and Gardeniae fructus were better in neuronal signaling. In conclusion, for treating BPSD, Scutellariae radix and Phellodendri chinrnsis cortex are the principal herbs while Coptidis rhizoma and Gardeniae fructus are the ancillary herbs.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

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Novel Combination of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Wang

Shi

2021

Preprint

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“…Serotonin and its receptors, particularly the HTR2A, are considered to play a potential role in cognitive behaviors and psychiatric conditions such as depression, schizophrenia, and AD [15] . A multitarget-directed ligand, acting on HTR2A and DRD2, exerting an anti-aggressive and antipsychotic activity, posing a promising strategy for the treatment of BPSD [16] . In our study, the active ingredients were selected as the docked compounds with DRD2 and HTR2A.…”

Section: Results Of Molecular Dockingmentioning

confidence: 99%

“…It has been demonstrated that serotoninergic, dopaminergic, and cholinergic systems are mainly involved in the pathogenesis of BPSD, and the role of HTR2A and DRD2 as therapeutic targets appear to be evident [16] . Our research utilized molecular docking to nd potential active ingredients with good binding activities to DRD2 and HTR2A.…”

Section: Discussionmentioning

confidence: 99%

Novel Compatibility of Huanglianjiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease1

Ma¹,

Wang²,

Du³

et al. 2020

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Background: Alzheimer's disease (AD) is characterized by progressive cognitive decline. Behavioral and psychological symptoms in dementia (BPSD) are another critical characterization of AD besides cognitive deficit. However, the pharmacological treatment of BPSD remains challenging. HuanglianJiedu decoction (HLJDD), which consists of four herbs, is applied to treat Alzheimer's disease in traditional Chinese medicine, especially AD with BPSD. While the frequently used compatibility of HLJDD, whose principal ingredient is Coptidis Rhizoma (Huang-lian, CR), may not be suitable for treating BPSD. Elucidating the mechanism underlying each herb is critical to HLJDD's pertinent compatibility.Methods: We utilized network pharmacology to analyze the herbs' targets and biological processes for treating BPSD in HLJDD and employed molecular docking to explore the binding activity between herbs' main active ingredients and neurotransmitter receptors. Results: Results showed that Scutellariae Radix (Huang-qin, SR) and Phellodendri Chinrnsis Cortex (Huang-bai, PCC) have better anti-BPSD effects than CR and Gardeniae Fructus (Zhi-zi, GF). SR has a better anti-neuroinflammation function, can better regulate blood vessels. PCC has a higher binding affinity with Dopamine D2 receptor (DRD2) and 5-hydroxytryptamine receptor 2A (HTR2A). CR and GF may be better for neuronal signaling.Conclusion: For treating BPSD, SR and PCC are the principal ingredients while CR and GF are the ancillary herbs.

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Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents

et al. 2021

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Background Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy. Methods Based on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT2A receptor model. Results Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3 μM) being more active than sarpogrelate (IC50 = 66.8 μM) and comparable with ketanserin (IC50 = 32.1 μM). Moreover, compounds 2–5, 9–11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. Conclusions Our study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.

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Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)

Cited by 9 publications

References 40 publications

Novel Combination of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Novel Combination of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Novel Compatibility of Huanglianjiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease1

Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents

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Multifunctional 6-fluoro-3-[3-(pyrrolidin-1-yl)propyl]-1,2-benzoxazoles targeting behavioral and psychological symptoms of dementia (BPSD)

Cited by 9 publications

References 40 publications

Novel Combination&nbsp;of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Novel Combination&nbsp;of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Novel Compatibility of Huanglianjiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease1

Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents

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Product

Resources

About

Novel Combination of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Novel Combination of HuanglianJiedu Decoction in Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease