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      Computational and Pharmacological Investigation of (E)-2-(4-Methoxybenzylidene)Cyclopentanone for Therapeutic Potential in Neurological Disorders

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          Abstract

          Purpose

          This study involved the computational and pharmacological evaluation of (E)-2-(4-methoxybenzylidene)cyclopentan-1-one (A2K10).

          Methods

          In silico studies were conducted through virtual screening. Morris water and Y-maze tests were conducted to evaluate Alzheimer’s disease. Acute epilepsy haloperidol,and hyperalgesia were used to calculate the epilepsy model, with Parkinson’s disease and mechanical allodynia at a dose of 1–10 mg/kg in the mouse model.

          Results

          A2K10 exhibited the highest binding affinity against α 7 nicotinic acetylcholine receptors (−256.02 kcal/mol). A2K10 decreased escape latency in the Morris water test during different trials. In the Y-maze test, A2K10 dose-dependently increased spontaneous alteration behavior, with maximum effect of 75.5%±0.86%. Furthermore, A2K10 delayed onset of pentylenetetrazole-induced myoclonic jerks and tonic–clonic seizures and decreased duration of tonic–clonic convulsions in mice, with maximum effect of 93.8±5.30, 77.8±2.91, and 12.9±1.99 seconds, respectively. In the haloperidol-induced Parkinson’s disease model, A2K10 significantly prolonged hanging time and reduced tardive dyskinesia. Moreover, A2K10 extended latency in hot-plate hyperalgesia and increased the paw-withdrawal threshold in mechanical allodynia. In toxicity studies, no mortality was observed.

          Conclusion

          Overall, the results indicated that A2K10 has potential as an anti-Alzheimer’s, antiepileptic, antiparkinsonian, and analgesic therapeutic compound.

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          Most cited references 24

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          Screening of Brazilian plant extracts for antioxidant activity by the use of DPPH free radical method.

          Brazilian plant extracts belonging to 16 species of 5 different families (71 extracts) were tested against the stable DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) free-radical. The ability to scavenge DPPH radical was measured in these experiments by the discoloration of the solution. Ginkgo biloba and rutin, commonly used as antioxidants for medical purposes, were used as standards. Based on our results, we can say that as a general rule the ethanol extracts of plants belonging to the Verbenaceae family showed lower EC(50) values than the other plant extracts. Among the partitions, the more polar ones (ethyl acetate and n-butanol) are those that generally have higher antioxidant activity (AA). Copyright 2001 John Wiley & Sons, Ltd.
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            The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation.

            The physiological regulation of the immune system encompasses comprehensive anti-inflammatory mechanisms that can be harnessed for the treatment of infectious and inflammatory disorders. Recent studies indicate that the vagal nerve, involved in control of heart rate, hormone secretion and gastrointestinal motility, is also an immunomodulator. In experimental models of inflammatory diseases, vagal nerve stimulation attenuates the production of proinflammatory cytokines and inhibits the inflammatory process. Acetylcholine, the principal neurotransmitter of the vagal nerve, controls immune cell functions via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). From a pharmacological perspective, nicotinic agonists are more efficient than acetylcholine at inhibiting the inflammatory signaling and the production of proinflammatory cytokines. This 'nicotinic anti-inflammatory pathway' may have clinical implications as treatment with nicotinic agonists can modulate the production of proinflammatory cytokines from immune cells. Nicotine has been tested in clinical trials as a treatment for inflammatory diseases such as ulcerative colitis, but the therapeutic potential of this mechanism is limited by the collateral toxicity of nicotine. Here, we review the recent advances that support the design of more specific receptor-selective nicotinic agonists that have anti-inflammatory effects while eluding its collateral toxicity.
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              Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships

              Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxibetc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                07 September 2020
                2020
                : 14
                : 3601-3614
                Affiliations
                [1 ]Riphah Institute of Pharmaceutical Sciences, Riphah International University , Islamabad, Pakistan
                [2 ]Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University , Alkharj, Saudi Arabia
                Author notes
                Correspondence: Arif-ullah Khan Riphah Institute of Pharmaceutical Sciences, Riphah International University , 7th Avenue, Sector G-7/4, Islamabad, PakistanTel +92-51-289-1835-38Fax +92-51-2891471, 2890690 Email arif.ullah@riphah.edu.pk
                Article
                234345
                10.2147/DDDT.S234345
                7490097
                © 2020 Farooq et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 12, Tables: 8, References: 26, Pages: 14
                Categories
                Original Research

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