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

Summary

Two new psychoactive substances, 4-methylphenmetrazine (4-MPM) and 3-methylphenmetrazine (3-MPM), have appeared on the recreational drug market following the earlier emergence of 3-fluorophenmetrazine. Analytical characterization of vendor samples confirmed the presence of 4-MPM in two samples and 3-MPM in one sample. In vitro transporter assays using rat brain synaptosomes tested the isomers' ability to inhibit uptake or stimulate release of dopamine, norepinephrine, and serotonin. The findings suggest that 2-MPM and 3-MPM will exhibit stimulant properties similar to phenmetrazine, whereas 4-MPM may display entactogen properties more similar to MDMA. Combining test purchases, analytical characterization, targeted synthesis, and pharmacological evaluation provides an effective approach for generating data on emerging substances.

Study at a glance

Abstract

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.