Molecular basis of the selective binding of MDMA enantiomers to the alpha4beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies.
Salomé Llabrés, Sara Garcia-Ratés, Edgar Cristóbal-Lecina, Antoni Riera, José Ignacio Borrell, Jorge Camarasa, David Pubill, F Javier Luque, Elena Escubedo
European journal of medicinal chemistry June 23, 2014 DOI: 10.1016/j.ejmech.2014.04.044 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | NGF-differentiated PC12 cells and α4β2 nicotinic acetylcholine receptors in radioligand binding assays |
| Interventions | (R)-MDMA (S)-MDMA |
| Measures | [3H]epibatidine radioligand binding assay, inhibition constant, Hill coefficient |
| Topics | MDMA |
| Keywords | Alpha4beta2 nicotinic receptor Enantioselective binding Molecular modelling Receptor up-regulation Stereoselective synthesis |
| Key findings | The MDMA enantiomers differ in their interaction with the α4β2 nicotinic receptor: (S)-MDMA has a 13-fold higher inhibition constant than (R)-MDMA, and (R)-MDMA up-regulates heteromeric nicotinic receptors in NGF-differentiated PC12 cells. The authors propose that these differences arise from distinct interactions of the substituents at MDMA's stereogenic center, providing a structural basis for enantiomer-specific psychostimulant profiles. |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 5
- Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine ACS Chemical Neuroscience July 12, 2018
- Applications and Potential of In Silico Approaches for Psychedelic Chemistry Molecules August 9, 2023
- Synthesis of R- and S-MDMA via nucleophilic ring-opening of homochiral N-tosylaziridines Australian Journal of Chemistry July 11, 2023
- The promise of psychedelic research Future Drug Discovery February 18, 2022
- 3,4-Methylenedioxymethamphetamine (MDMA) Alters Synaptic Dopamine Release in the Dorsal Striatum Through Nicotinic Receptors and DAT Inhibition. Neuroscience May 1, 2018
Cites 9
- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class Journal of Medicinal Chemistry October 1, 1986
- Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain. Biochemical Pharmacology July 15, 1987
- Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) EnantiomersIn Vitroand in the MPTP-Lesioned Primate:R-MDMA Reduces Severity of Dyskinesia, WhereasS-MDMA Extends Duration of ON-Time Journal of Neuroscience May 11, 2011
- Differential effects of intravenous R,S‐(±)‐3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)‐ and R(−)‐enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core Journal of Neurochemistry January 22, 2007
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