title: Molecular basis of the selective binding of MDMA enantiomers to the alpha4beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies.
abstract: 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 [(3)H]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 [(3)H]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.
authors.affiliation: Department of Physical Chemistry and Institut of Biomedicine (IBUB), Faculty of Pharmacy, Campus de l'Alimentació Torribera, University of Barcelona, Avda. Prat de la Riba 171, Santa Coloma de Gramenet, E-08921 Barcelona, Spain.
authors.forename: Salomé
authors.initials: S
authors.lastname: Llabrés
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry and Institut of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Nucli Univ. Pedralbes, E-08028 Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: García-Ratés
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Baldiri i Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Edgar
authors.initials: E
authors.lastname: Cristóbal-Lecina
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Baldiri i Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Riera
authors.affiliation: IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Borrell
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry and Institut of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Nucli Univ. Pedralbes, E-08028 Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Camarasa
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry and Institut of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Nucli Univ. Pedralbes, E-08028 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pubill
authors.affiliation: Department of Physical Chemistry and Institut of Biomedicine (IBUB), Faculty of Pharmacy, Campus de l'Alimentació Torribera, University of Barcelona, Avda. Prat de la Riba 171, Santa Coloma de Gramenet, E-08921 Barcelona, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry and Institut of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Nucli Univ. Pedralbes, E-08028 Barcelona, Spain. Electronic address: eescubedo@ub.edu.
authors.forename: Elena
authors.initials: E
authors.lastname: Escubedo
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D016716:PC12 Cells; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D015104:3,4-Methylenedioxyamphetamine; C051800:3,4-methylenedioxyethamphetamine
keywords: Alpha4Beta2 nicotinic receptor; Enantioselective binding; MDMA; Molecular modelling; Receptor up-regulation; Stereoselective synthesis