Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties

Ganesh, Thota; Banik, Avijit; Dingledine, Raymond; Wang, Wenyi; Amaradhi, Radhika

doi:10.1021/acs.molpharmaceut.8b00764

Cited by 20 publications

(21 citation statements)

References 36 publications

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“…Prior to administering TG8-260 to animals, we investigated its in vitro inflammation modulating properties and found that TG8-260 reverses the change in expression of inflammatory mediators induced by the combination of LPS and EP2 activation, consistent with other EP2 receptor antagonists created in our laboratory [1,2,21,28,29]. Although IL-10 displays pleiotropic effects it is largely an anti-inflammatory mediator and therefore enhancing IL-10 expression will quell inflammation.…”

Section: Discussionsupporting

confidence: 55%

A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats

et al. 2021

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Prostaglandin-E 2 (PGE 2 ), an important mediator of inflammation, achieves its functions via four different G protein-coupled receptors (EP1, EP2, EP3, and EP4). We previously demonstrated that the EP2 receptor plays a proinflammatory and neurodegenerative role after status epilepticus (SE). We recently developed TG8-260 as a second-generation highly potent and selective EP2 antagonist. Here, we investigate whether TG8-260 is anti-inflammatory and combats neuropathology caused by pilocarpineinduced SE in rats. Adult male Sprague-Dawley rats were injected subcutaneously with pilocarpine (380-400 mg/kg) to induce SE. Following 60 min of SE, the rats were administered three doses of TG8-260 or vehicle and were allowed to recover. Neurodegeneration, neuroinflammation, gliosis, and blood-brain barrier (BBB) integrity were examined 4 days after SE. The results confirmed that pilocarpine-induced SE results in hippocampal neurodegeneration and a robust inflammatory response that persists days after SE. Furthermore, inhibition of the EP2 receptor by TG8-260 administered beginning 2 h after SE significantly reduced hippocampal neuroinflammation and gliosis but, in distinction to the earlier generation EP2 antagonist, did not mitigate neuronal injury or BBB breakdown. Thus, attenuation of neuroinflammation and gliosis is a common feature of EP2 inhibition following SE.

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Section: Discussionsupporting

confidence: 55%

A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats

et al. 2021

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“…It could be predicted from the table that all of the eugenol based derivatives shown logP values within the limit. Lesser blood–brain barrier (BBB) access and poor membrane permeability is associated with a larger rate of tPSA (> 145 Å 2 ) [32]. Nearly all of the synthesized derivatives exhibited acceptable values of tPSA within a range of 35–140 (Table 4).…”

Section: Resultsmentioning

confidence: 99%

Lead optimization for promising monoamine oxidase inhibitor from eugenol for the treatment of neurological disorder: synthesis and in silico based study

2019

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Natural based inhibitors of monoamine oxidase are promising drug candidates for the treatment of several neurodegenerative and neuropsychological disorders including depression, anxiety, Parkinson’s disease and Alzheimer’s disease. In the present study we designed and synthesized the eugenol based derivatives and investigated them for human MAO inhibitory potential as promising candidates for therapeutics of neurological disorders. Moreover, radical scavenging activity of designed derivatives was tested by and H 2 O 2 and DPPH scavenging methods. Eugenol based derivatives were designed and synthesized for human MAO inhibitory action. The in silico and in vitro models were utilized for the evaluation of hMAO inhibition. The insight into molecular interactions among the compounds and both hMAO-A and hMAO-B active site was achieved by molecular docking studies. The two spectrophotometric titrations techniques were used to evaluate antioxidant potential. Compounds 5b and 16 were found as most active hMAO-A inhibitors with IC 50 values of 5.989 ± 0.007 µM and 7.348 ± 0.027 µM respectively, through an appreciable selectivity index value of 0.19 and 0.14 respectively. In case of hMAO-B inhibition compounds 13a and 13b were found as most active hMAO-B inhibitors with IC 50 values of 7.494 ± 0.014 µM and 9.183 ± 0.034 µM receptively and outstanding value of selectivity index of 5.14 and 5.72 respectively. Radical scavenging assay showed that compounds 5b , 5a , 9b , 9a were active antioxidants. The findings of present study indicated excellent correlation among dry lab and wet lab hMAO inhibitory experiments. Interestingly, the compounds exhibiting better MAO inhibition activity was also appeared as good antioxidant agents.

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“…In addition, MDSCs expressed high levels of COX2 and were a major source of PGE2 secretion in human cancer (Obermajer et al, 2011). Hence, inhibition of PGE2 production using non-selective or COX2-selective blockers as well as selective antagonists of PGE2 receptors (Ganesh et al, 2018;Markovic et al, 2017) is likely to prevent MDSC-related MDR.…”

Section: Therapeutic Approaches Targeting Mdscsmentioning

confidence: 99%

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

Erin

Grahovac

Brozović

et al. 2020

Drug Resistance Updates

345

187

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties

Cited by 20 publications

References 36 publications

A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats

A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats

Lead optimization for promising monoamine oxidase inhibitor from eugenol for the treatment of neurological disorder: synthesis and in silico based study

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

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