The syntheses, characterization and in vitro metabolism of nitracaine, methoxypiperamide and mephtetramine

Abstract

Three legal highs; nitracaine (3-(diethylamino)-2,2-dimethylpropyl 4-nitrobenzoate), methoxypiperamide (MEOP, (4-methoxyphenyl)(4-methylpiperazin-1-yl)methanone) and mephtetramine (MTTA, 2-((methylamino)methyl)-3,4-dihydronaphthalen-1(2H)-one) appeared in 2013 as new psychoactive substances (NPS) on Internet websites selling 'research chemicals'. These compounds were synthesized and analyzed via our synthesize, analyze, and metabolize (SAM) protocol. Nitracaine was synthesized by the transesterification of methyl 4-nitrobenzoate with 3-(diethylamino)-2,2-dimethylpropan-1-ol. Methoxypiperamide was synthesized by the reaction of 4-methoxybenzoyl chloride with 1-methylpiperazine, and mephtetramine through the Mannich reaction of 1-tetralone with paraformaldehyde and methylamine hydrochloride. Each compound was characterized by nuclear magnetic resonance (NMR), gas chromatography with electron impact mass spectrometry (GC-EIMS), liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS), and high resolution electrospray ionization mass spectrometry (HR-ESI-MS). A sample of nitracaine was also test-purchased from an Internet vendor and its structure confirmed by GC-EIMS and LC-ESI-MS. Finally, the in vitro metabolism of the nitracaine, mephtetramine, and methoxypiperamide was investigated, using a human microsomal liver extract, in order to tentatively identify potential metabolites that may be encountered in the analysis of biological samples in clinical or toxicology labs. The use of our SAM protocol highlights the ability of academic research labs to quickly respond to and disseminate information about emerging NPS.

The new drug phenomenon

“…The synthesis and characterization of nitracaine (3‐(diethylamino)‐2,2‐dimethylpropyl 4‐nitrobenzoate), methoxypiperamide (4‐methoxyphenyl) (4‐methylpiperazin‐1‐yl)methanone) and mephtetramine (2‐((methylamino)methyl)‐3,4‐dihydronaphthalen‐1(2 H )‐one) was described by Power et al who encountered these substances as ‘research chemicals’ from online vendors in 2013. The authors extended the work to the incubation with pooled human liver microsomes to assess their transformation by LC‐MS . The presence of nitracaine was also confirmed in a test purchase.…”

Antibacterial and antitubercular evaluation of dihydronaphthalenone‐indole hybrid analogs

“…Alex and coworkers designed naphthalenyl dihydroimidazoles with the inspiration of napamezole‐based hybrid library, which suggested that the potential antidepressants can display combined α 2 ‐adrenoceptor antagonist and monoamine uptake inhibitor properties . Mephtetramine represent yet another generation of new psychoactive substance . Liu et al., discovered a series of novel naphthalenyl pyrimidinones as potent HIV‐1 inhibitors (Figure ).…”

Metabolism study and toxicological determination of mephtetramine in biological samples by liquid chromatography coupled with high‐resolution mass spectrometry

“…Other isobaric compounds were taken in to account for the raw formula C 12 H 13 NO. Power et al 6 postulated the formation of a di‐hydro isoxazole derivative, obtained by N ‐oxidation, cyclization, and dehydration. This hypothesis was discarded because of the presence of the fragment ion at m / z 170.0965, not compatible with the structure proposed.…”