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

Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors

“…36, 37 Commercially available ( R )- or ( S )- t -butylsulfinamides ( R- and S - 85 ) were condensed with 76 . Low-temperature reduction of the imine with NaBH 4 afforded the expected ( R,R )-diastereomer ( R,R) - 86 (when ( R) - 85 was used), and ( S,S )-diastereomer ( S,S )- 86 (when S - 85 was used) in satisfactory (>7:1) diastereomeric ratios.…”

“…As derivatives of 78 proved difficult to resolve into their enantiomers, an asymmetric synthesis of the two enantiomers of 19 (Scheme ) was developed, based on the Ellman auxiliary. , Commercially available ( R )- or ( S )- t -butylsulfinamides ( R- and S - 85 ) were condensed with 76 . Low-temperature reduction of the imine with NaBH 4 afforded the expected ( R,R )-diastereomer ( R,R) - 86 (when ( R) - 85 was used), and ( S,S )-diastereomer ( S,S )- 86 (when ( S )- 85 was used) in satisfactory (>7:1) diastereomeric ratios.…”

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

“…In 2014, Escubedo and co-workers reported a similar approach using Ellman’s sulfonamide as the chiral auxiliary (Figure 3B). 57 …”

“…In 2014, Escubedo and co-workers reported a similar approach using Ellman's sulfonamide as the chiral auxiliary (Figure 3B). 57 The chiral pool has also been exploited to produce enantiopure MDMA. Using a method developed by Nenajdenko and co-workers, 58 (S)-alaninol (23) can be protected and converted to the aziridine 24.…”

“…Palladium-catalyzed hydrogenolysis afforded MDA ( 14 ), which was converted to MDMA after reduction of the formamide. In 2014, Escubedo and co-workers reported a similar approach using Ellman’s sulfonamide as the chiral auxiliary (Figure B) …”