Synthesis, analytical characterization, and monoamine transporter activity of the new psychoactive substance 4‐methylphenmetrazine (4‐MPM), with differentiation from its ortho‐ and meta‐ positional isomers

• Published in: Drug testing and analysis 2018-09, Vol.10 (9), p.1404-1416
• Main Authors: McLaughlin, Gavin, Baumann, Michael H., Kavanagh, Pierce V., Morris, Noreen, Power, John D., Dowling, Geraldine, Twamley, Brendan, O'Brien, John, Hessman, Gary, Westphal, Folker, Walther, Donna, Brandt, Simon D.
• Format: Article
• Language: English
• Subjects: Animals; Brain Chemistry - drug effects; Central Nervous System Stimulants - analysis; Chromatography, High Pressure Liquid; Designer Drugs - analysis; Dopamine; Dopamine Plasma Membrane Transport Proteins - analysis; Drug testing; Ecstasy; Fluorophenmetrazine; Gas Chromatography-Mass Spectrometry; Illicit Drugs - analysis; Indicators and Reagents; Isomerism; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; monoamine transporters; new psychoactive substances; Norepinephrine Plasma Membrane Transport Proteins - analysis; phenmetrazine; Phenmetrazine - analogs & derivatives; Phenmetrazine - analysis; psychostimulants; Psychotropic drugs; Rats; Rats, Sprague-Dawley; Reference Standards; RNA-Binding Proteins - analysis; Synaptosomes - drug effects; Synaptosomes - metabolism; Vesicular Monoamine Transport Proteins - drug effects
• ISSN: 1942-7603; 1942-7611
• DOI: 10.1002/dta.2396

The availability of new psychoactive substances (NPS) on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM), and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization, and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic, and mass spectrometric platforms. Pharmacological studies were conducted to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to 3,4‐methylenedioxymethamphetamine (MDMA). The combination of test purchases, analytical characterization, targeted organic synthesis, and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace. Two phenmetrazine analogs, namely 4‐methylphenmetrazine (4‐MPM), and 3‐methylphenmetrazine (3‐MPM) have been encountered on the new psychoactive substances market. The syntheses, analytical characterization, and pharmacological evaluation of 2‐, 3‐ and 4‐MPM are described. The results from in vitro transporter assays (DAT, NET, and SERT) in rat brain synaptosomes suggest that 2‐ and 3‐MPM display stimulant‐like effects similar to the parent compound phenmetrazine whereas 4‐MPM was more similar to 3,4‐methylenedioxymethamphetamine (MDMA).