PMID- 24942641
OWN - NLM
STAT- MEDLINE
DCOM- 20150330
LR  - 20161125
IS  - 1768-3254 (Electronic)
IS  - 0223-5234 (Linking)
VI  - 81
DP  - 2014 Jun 23
TI  - Molecular basis of the selective binding of MDMA enantiomers to the alpha4beta2 
      nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic 
      studies.
PG  - 35-46
LID - S0223-5234(14)00365-1 [pii]
LID - 10.1016/j.ejmech.2014.04.044 [doi]
AB  - The alpha4beta2 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 alpha4beta2 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 alpha4beta2 nAChR subtype.
CI  - Copyright (c) 2014 Elsevier Masson SAS. All rights reserved.
FAU - Llabres, Salome
AU  - Llabres S
AD  - Department of Physical Chemistry and Institut of Biomedicine (IBUB), Faculty of 
      Pharmacy, Campus de l'Alimentacio Torribera, University of Barcelona, Avda. Prat 
      de la Riba 171, Santa Coloma de Gramenet, E-08921 Barcelona, Spain.
FAU - Garcia-Rates, Sara
AU  - Garcia-Rates S
AD  - Department of Pharmacology and Therapeutic Chemistry and Institut of Biomedicine 
      (IBUB), Faculty of Pharmacy, University of Barcelona, Nucli Univ. Pedralbes, 
      E-08028 Barcelona, Spain.
FAU - Cristobal-Lecina, Edgar
AU  - Cristobal-Lecina E
AD  - Institute for Research in Biomedicine (IRB Barcelona), Baldiri i Reixac, 10, 
      08028 Barcelona, Spain.
FAU - Riera, Antoni
AU  - Riera A
AD  - Institute for Research in Biomedicine (IRB Barcelona), Baldiri i Reixac, 10, 
      08028 Barcelona, Spain.
FAU - Borrell, Jose Ignacio
AU  - Borrell JI
AD  - IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, E-08017 
      Barcelona, Spain.
FAU - Camarasa, Jorge
AU  - Camarasa J
AD  - Department of Pharmacology and Therapeutic Chemistry and Institut of Biomedicine 
      (IBUB), Faculty of Pharmacy, University of Barcelona, Nucli Univ. Pedralbes, 
      E-08028 Barcelona, Spain.
FAU - Pubill, David
AU  - Pubill D
AD  - Department of Pharmacology and Therapeutic Chemistry and Institut of Biomedicine 
      (IBUB), Faculty of Pharmacy, University of Barcelona, Nucli Univ. Pedralbes, 
      E-08028 Barcelona, Spain.
FAU - Luque, F Javier
AU  - Luque FJ
AD  - Department of Physical Chemistry and Institut of Biomedicine (IBUB), Faculty of 
      Pharmacy, Campus de l'Alimentacio Torribera, University of Barcelona, Avda. Prat 
      de la Riba 171, Santa Coloma de Gramenet, E-08921 Barcelona, Spain.
FAU - Escubedo, Elena
AU  - Escubedo E
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140502
PL  - France
TA  - Eur J Med Chem
JT  - European journal of medicinal chemistry
JID - 0420510
RN  - 0 (Receptors, Nicotinic)
RN  - 0 (nicotinic receptor alpha4beta2)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - ML1I4KK67B (3,4-methylenedioxyethamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/*analogs & derivatives/chemical 
      synthesis/chemistry/metabolism/pharmacology
MH  - Animals
MH  - Binding Sites/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Molecular Structure
MH  - PC12 Cells
MH  - Rats
MH  - Receptors, Nicotinic/*metabolism
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - Alpha4Beta2 nicotinic receptor
OT  - Enantioselective binding
OT  - MDMA
OT  - Molecular modelling
OT  - Receptor up-regulation
OT  - Stereoselective synthesis
EDAT- 2014/06/20 06:00
MHDA- 2015/03/31 06:00
CRDT- 2014/06/20 06:00
PHST- 2014/06/20 06:00 [entrez]
PHST- 2014/06/20 06:00 [pubmed]
PHST- 2015/03/31 06:00 [medline]
AID - S0223-5234(14)00365-1 [pii]
AID - 10.1016/j.ejmech.2014.04.044 [doi]
PST - ppublish
SO  - Eur J Med Chem. 2014 Jun 23;81:35-46. doi: 10.1016/j.ejmech.2014.04.044. Epub 
      2014 May 2.