Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold

Kim, Minsoo; Truss, Myles; Pagare, Piyusha P.; Essandoh, Martha A; Zhang, Yan; Williams, Dwight A.

doi:10.1016/j.bmcl.2020.127511

Cited by 5 publications

(5 citation statements)

References 16 publications

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“…151,152 Therebefore, the proposed mechanisms by which I. cylindrica provides its neuroprotective attributes are the 'antioxidant' and 'receptor inhibition' mechanisms 115,139,151,152 arising from the main phytochemicals of the plant (polyphenols, flavonoids, and chromones), these provide important biological activities within the brain cells including the improvement of antioxidant status, tissue repair, decreased inflammation and apoptosis, improvement of brain cell biology, 37,39 and binding and inhibition of VGSCs and receptors (eg, 5-HT2B) by chromones 1 and 2. 37,38,153 These in turn result in the alleviation of brain histopathology, seizure control, and alleviation of cognitive deficits in our mutant D. melanogaster model of epilepsy. This concurs with previous studies that have shown novel therapeutic strategies including 'natural antioxidant therapy' using plant extracts to be able to prevent epileptogenesis, modify epileptic phenotypes, and attenuate the associated neurological deficits and defects in epileptic animals.…”

Section: Discussionmentioning

confidence: 83%

Attenuation of Seizures, Cognitive Deficits, and Brain Histopathology by Phytochemicals of Imperata cylindrica (L.) P. Beauv (Poaceae) in Acute and Chronic Mutant Drosophila melanogaster Epilepsy Models

Ssempijja

Dare

Bukenya

et al. 2023

J Evid Based Complementary Altern Med

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Imperata cylindrica is a globally distributed plant known for its antiepileptic attributes, but there is a scarcity of robust evidence for its efficacy. The study investigated neuroprotective attributes of Imperata cylindrica root extract on neuropathological features of epilepsy in a Drosophila melanogaster mutant model of epilepsy. It was conducted on 10-day-old (at the initiation of study) male post-eclosion bang-senseless paralytic Drosophila ( parabss1) involved acute (1-3 h) and chronic (6-18 days) experiments; n = 50 flies per group (convulsions tests); n = 100 flies per group (learning/memory tests and histological examination). Administrations were done in 1 g standard fly food, per os. The mutant flies of study ( parabss1) showed marked age-dependent progressive brain neurodegeneration and axonal degeneration, significant (P < 0.05) bang sensitivity and convulsions, and cognitive deficits due to up-regulation of the paralytic gene in our mutants. The neuropathological findings were significantly (P < 0.05) alleviated in dose and duration-dependent fashions to near normal/normal after acute and chronic treatment with extract similar to sodium valproate. Therefore, para is expressed in neurons of brain tissues in our mutant flies to bring about epilepsy phenotypes and behaviors of the current juvenile and old-adult mutant D. melanogaster models of epilepsy. The herb exerts neuroprotection by anticonvulsant and antiepileptogenic mechanisms in mutant D. melanogaster due to plant flavonoids, polyphenols, and chromones (1 and 2) which exert antioxidative and receptor or voltage-gated sodium ion channels’ inhibitory properties, and thus causing reduced inflammation and apoptosis, increased tissue repair, and improved cell biology in the brain of mutant flies. The methanol root extract provides anticonvulsant and antiepileptogenic medicinal values which protect epileptic D. melanogaster. Therefore, the herb should be advanced for more experimental and clinical studies to confirm its efficacy in treating epilepsy.

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Section: Discussionmentioning

confidence: 83%

Attenuation of Seizures, Cognitive Deficits, and Brain Histopathology by Phytochemicals of Imperata cylindrica (L.) P. Beauv (Poaceae) in Acute and Chronic Mutant Drosophila melanogaster Epilepsy Models

Ssempijja

Dare

Bukenya

et al. 2023

J Evid Based Complementary Altern Med

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“…There are many studies using the pKi value as an affinity value of compounds, in terms of affinity for serotonin receptors [ 37 , 38 , 39 , 40 , 41 ] or other biological targets [ 42 , 43 , 44 , 45 , 46 ]. Defined endpoint is a parameter that enables a comparison of its value between other studies.…”

Section: Resultsmentioning

confidence: 99%

Do AutoML-Based QSAR Models Fulfill OECD Principles for Regulatory Assessment? A 5-HT1A Receptor Case

et al. 2022

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The drug discovery and development process requires a lot of time, financial, and workforce resources. Any reduction in these burdens might benefit all stakeholders in the healthcare domain, including patients, government, and companies. One of the critical stages in drug discovery is a selection of molecular structures with a strong affinity to a particular molecular target. The possible solution is the development of predictive models and their application in the screening process, but due to the complexity of the problem, simple and statistical models might not be sufficient for practical application. The manuscript presents the best-in-class predictive model for the serotonin 1A receptor affinity and its validation according to the Organization for Economic Co-operation and Development guidelines for regulatory purposes. The model was developed based on a database with close to 9500 molecules by using an automatic machine learning tool (AutoML). The model selection was conducted based on the Akaike information criterion value and 10-fold cross-validation routine, and later good predictive ability was confirmed with an additional external validation dataset with over 700 molecules. Moreover, the multi-start technique was applied to test if an automatic model development procedure results in reliable results.

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“…A subsequent SAR study on a series of synthesized and 5-HPEC's natural analogs was performed and showed that the most potent analog, 5-hydroxy-2-(2phenylpropyl)chromone (5-HPPC) (24, Figure 7), exhibited a 10-fold improvement in the 5-HT2BR affinity (Ki = 251 nM) and was able to maintain the 5-HT2BR antagonism [139]. Recently, further optimization of 5-HPPC guided by molecular modeling approaches helped to identify 5-hydroxy-2-(3-(3-cyanophenyl)propyl)chromone (5-HCPC) (25, Figure 7), which exhibited an improved binding affinity (Ki = 79 nM) compared with 5-HPPC and maintained inhibitory activity (IC50 = 6310 nM in calcium flux assay) at the 5-HT2BR, as well as selectivity over the 5-HT2AR and the 5-HT2CR [140]. It is worth mentioning that In order to improve oral potency and keep high affinity, the researchers further optimized guanidine 20 by taking the balance between lipophilicity and polar surface area into consideration [136].…”

Section: Chromone Derivativesmentioning

confidence: 99%

“…A subsequent SAR study on a series of synthesized and 5-HPEC's natural analogs was performed and showed that the most potent analog, 5-hydroxy-2-(2phenylpropyl)chromone (5-HPPC) (24, Figure 7), exhibited a 10-fold improvement in the 5-HT 2B R affinity (K i = 251 nM) and was able to maintain the 5-HT 2B R antagonism [139]. Recently, further optimization of 5-HPPC guided by molecular modeling approaches helped to identify 5-hydroxy-2-(3-(3-cyanophenyl)propyl)chromone (5-HCPC) (25, Figure 7), which exhibited an improved binding affinity (K i = 79 nM) compared with 5-HPPC and maintained inhibitory activity (IC 50 = 6310 nM in calcium flux assay) at the 5-HT 2B R, as well as selectivity over the 5-HT 2A R and the 5-HT 2C R [140]. It is worth mentioning that these chromone derivatives are non-nitrogenous, which are different from the typical nitrogencontaining ligands of the 5-HT 2B R. Although the binding modes of this type of ligands were predicted by molecular docking, the evidence was insufficient to effectively demonstrate that these non-nitrogenous ligands bind to the orthosteric site of the 5-HT 2B R. Considering the relatively weak cellular activity of 5-HCPC with much stronger binding affinity, it is not possible to exclude the possibility that they represent allosteric-site binders.…”

Section: Chromone Derivativesmentioning

confidence: 99%

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Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

et al. 2021

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Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas.

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Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold

Cited by 5 publications

References 16 publications

Attenuation of Seizures, Cognitive Deficits, and Brain Histopathology by Phytochemicals of Imperata cylindrica (L.) P. Beauv (Poaceae) in Acute and Chronic Mutant Drosophila melanogaster Epilepsy Models

Attenuation of Seizures, Cognitive Deficits, and Brain Histopathology by Phytochemicals of Imperata cylindrica (L.) P. Beauv (Poaceae) in Acute and Chronic Mutant Drosophila melanogaster Epilepsy Models

Do AutoML-Based QSAR Models Fulfill OECD Principles for Regulatory Assessment? A 5-HT1A Receptor Case

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

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