Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/111900
Title: Molecular basis of the selective binding of MDMA enantiomers to the Alpha4Beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies
Author: Llabrés Prat, Salomé
García-Ratés, Sara
Cristóbal Lecina, Edgar
Riera i Escalé, Antoni
Borrell, José Ignacio
Camarasa García, Jordi
Pubill Sánchez, David
Luque Garriga, F. Xavier
Escubedo Rafa, Elena
Keywords: Receptors nicotínics
Amfetamines
Èxtasi (Droga)
Estructura molecular
Nicotinic receptors
Amphetamines
Ecstasy (Drug)
Molecular structure
Issue Date: 2-May-2014
Publisher: Elsevier Masson SAS
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 [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 center of MDMA. The results provide a basis to explore the distinct psychostimulant profiles of the MDMA enantiomers mediated by the α4β2 nAChR subtype.
Note: Versió postprint del document publicat a: https://doi.org/10.1016/j.ejmech.2014.04.044
It is part of: European Journal of Medicinal Chemistry, 2014, vol. 81, p. 35-46
Related resource: https://doi.org/10.1016/j.ejmech.2014.04.044
URI: http://hdl.handle.net/2445/111900
ISSN: 0223-5234
Appears in Collections:Articles publicats en revistes (Química Inorgànica i Orgànica)

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