Molecular basis of the selective binding of MDMA enantiomers to the Alpha4Beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies
| العنوان: | Molecular basis of the selective binding of MDMA enantiomers to the Alpha4Beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies |
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| المؤلفون: | Sara Garcia-Ratés, Antoni Riera, Salomé Llabrés, Jorge Camarasa, José I. Borrell, David Pubill, Elena Escubedo, Edgar Cristóbal-Lecina, F. Javier Luque |
| المساهمون: | Universitat de Barcelona, Universitat Ramon Llull. IQS |
| المصدر: | Recercat. Dipósit de la Recerca de Catalunya instname RECERCAT (Dipòsit de la Recerca de Catalunya) Dipòsit Digital de la UB Universidad de Barcelona Recercat: Dipósit de la Recerca de Catalunya Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| بيانات النشر: | Elsevier Masson SAS, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | MDMA, Stereochemistry, Receptors nicotínics, Receptor Up-Regulation, Receptors, Nicotinic, PC12 Cells, Nicotina--Receptors, Structure-Activity Relationship, Ecstasy (Drug), Drug Discovery, mental disorders, medicine, Animals, Receptor up-regulation, Alpha4Beta2 nicotinic receptor, 3,4-Methylenedioxyamphetamine, 54 - Química, Pharmacology, Binding Sites, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Organic Chemistry, Estructura molecular, Amphetamines, Stereoselective synthesis, Stereoisomerism, Èxtasi (Droga), General Medicine, Enantioselective binding, Amfetamines, Radioligand Assay, Rats, Nicotinic acetylcholine receptor, Nicotinic agonist, Docking (molecular), Epibatidine, Nicotinic receptors, Molecular modelling, Enantiomer, Molecular structure, psychological phenomena and processes, medicine.drug |
| الوصف: | The α4β2 nicotinic acetylcholine receptor (nAChR) is a molecular target of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug also known as ecstasy, and it modulates the MDMA-mediated reinforcing properties. However, the enantioselective preference of the α4β2 nAChR subtype still remains unknown. Since the two enantiomers exhibit different pharmacological profiles and stereoselective metabolism, the aim of this study is to assess a possible difference in the interaction of the MDMA enantiomers with this nAChR subtype. To this end, we report a novel simple, yet highly efficient enantioselective synthesis of the MDMA enantiomers, in which the key step is the diastereoselective reduction of imides derived from optically pure tert-butylsulfinamide. The enantioselective binding to the receptor is examined using [3H]epibatidine in a radioligand assay. Even though the two enantiomers induced a concentration-dependent binding displacement, (S)-MDMA has an inhibition constant 13-fold higher than (R)-MDMA, which shows a Hill's coefficient not significantly different from unity, implying a competitive interaction. Furthermore, when NGF-differentiated PC12 cells were pretreated with the compounds, a significant increase in binding of [3H]epibatidine was found for (R)-MDMA, indicating up-regulation of heteromeric nAChR in the cell surface. Finally, docking and molecular dynamics studies have been used to identify the binding mode of the two enantiomers, which provides a structural basis to justify the differences in affinity from the differential interactions played by the substituents at the stereogenic centre of MDMA. The results provide a basis to explore the distinct psychostimulant profiles of the MDMA enantiomers mediated by the α4β2 nAChR subtype. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f8cf27628087816c4487370a076d4ac9 http://hdl.handle.net/2445/111900 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f8cf27628087816c4487370a076d4ac9 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |