Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay Development
The inhibitory effects of two novel lophine derivatives were unexpectedly discovered during the development of a chemiluminescent monoacylglycerol lipase (MAGL) assay. The proposed lophine derivatives were found to exhibit concentration-dependent inhibitory effects on MAGL with the octanoic and palm...
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| Language: | English |
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MDPI AG
2025-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/30/7/1605 |
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| author | Roberta Ottria Silvana Casati Ornella Xynomilakis Aleksandar Veselinović Pierangela Ciuffreda |
| author_facet | Roberta Ottria Silvana Casati Ornella Xynomilakis Aleksandar Veselinović Pierangela Ciuffreda |
| author_sort | Roberta Ottria |
| collection | DOAJ |
| description | The inhibitory effects of two novel lophine derivatives were unexpectedly discovered during the development of a chemiluminescent monoacylglycerol lipase (MAGL) assay. The proposed lophine derivatives were found to exhibit concentration-dependent inhibitory effects on MAGL with the octanoic and palmitic acid esters of 2-(4-hydroxyphenyl)-4,5-diphenylimidazole showing the strongest activity. Reversibility assays using a fluorometric method confirmed that these compounds interact with MAGL in a stable, irreversible manner. To further investigate their mode of interaction, docking studies were performed, supporting the hypothesis that compounds <b>3</b> and <b>4</b> may act as competitive and irreversible inhibitors. Lophine derivatives were initially designed and synthesized as potential chemiluminescence pro-enhancers. However, assay optimization revealed no signal production upon MAGL hydrolysis, precluding their use as chemiluminescent probes. These findings suggest that lophine is a promising candidate for the development of MAGL inhibitors, although further optimization is needed to enhance binding affinity and selectivity. |
| format | Article |
| id | doaj-art-23f673b44c5e48d4a7f9a2e0704ebe07 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-23f673b44c5e48d4a7f9a2e0704ebe072025-08-20T03:08:53ZengMDPI AGMolecules1420-30492025-04-01307160510.3390/molecules30071605Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay DevelopmentRoberta Ottria0Silvana Casati1Ornella Xynomilakis2Aleksandar Veselinović3Pierangela Ciuffreda4Dipartimento di Scienze Biomediche e Cliniche, Università degli Studi di Milano, 20157 Milano, ItalyDipartimento di Scienze Biomediche e Cliniche, Università degli Studi di Milano, 20157 Milano, ItalyDipartimento di Scienze Biomediche e Cliniche, Università degli Studi di Milano, 20157 Milano, ItalyDepartment of Chemistry, Faculty of Medicine, University of Niš, Blvd. Dr. Zorana Đinđića 81, 18000 Niš, SerbiaDipartimento di Scienze Biomediche e Cliniche, Università degli Studi di Milano, 20157 Milano, ItalyThe inhibitory effects of two novel lophine derivatives were unexpectedly discovered during the development of a chemiluminescent monoacylglycerol lipase (MAGL) assay. The proposed lophine derivatives were found to exhibit concentration-dependent inhibitory effects on MAGL with the octanoic and palmitic acid esters of 2-(4-hydroxyphenyl)-4,5-diphenylimidazole showing the strongest activity. Reversibility assays using a fluorometric method confirmed that these compounds interact with MAGL in a stable, irreversible manner. To further investigate their mode of interaction, docking studies were performed, supporting the hypothesis that compounds <b>3</b> and <b>4</b> may act as competitive and irreversible inhibitors. Lophine derivatives were initially designed and synthesized as potential chemiluminescence pro-enhancers. However, assay optimization revealed no signal production upon MAGL hydrolysis, precluding their use as chemiluminescent probes. These findings suggest that lophine is a promising candidate for the development of MAGL inhibitors, although further optimization is needed to enhance binding affinity and selectivity.https://www.mdpi.com/1420-3049/30/7/1605lophine derivativesmonoacylglycerol lipaseMAGLchemiluminescence assayenhancersinhibitors |
| spellingShingle | Roberta Ottria Silvana Casati Ornella Xynomilakis Aleksandar Veselinović Pierangela Ciuffreda Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay Development Molecules lophine derivatives monoacylglycerol lipase MAGL chemiluminescence assay enhancers inhibitors |
| title | Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay Development |
| title_full | Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay Development |
| title_fullStr | Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay Development |
| title_full_unstemmed | Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay Development |
| title_short | Discovery of MAGL Inhibition by Lophine Derivatives: An Unexpected Finding from Chemiluminescent Assay Development |
| title_sort | discovery of magl inhibition by lophine derivatives an unexpected finding from chemiluminescent assay development |
| topic | lophine derivatives monoacylglycerol lipase MAGL chemiluminescence assay enhancers inhibitors |
| url | https://www.mdpi.com/1420-3049/30/7/1605 |
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