'Second Generation' Mephedrone Analogs, 4-MEC and 4-MePPP, Differentially Affect Monoamine Transporter Function

Authors/others:Saha, Kusumika; Partilla, John S; Lehner, Kurt R; Seddik, Amir; Stockner, Thomas; Holy, Marion; Sandtner, Walter; Ecker, Gerhard F; Sitte, Harald H; Baumann, Michael H

The nonmedical use of synthetic cathinones is increasing on a global scale. 4-Methyl-N-methylcathinone (mephedrone) is a popular synthetic cathinone that is now illegal in the United States and other countries. Since the legislative ban on mephedrone, a number of 'second generation' analogs have appeared in the street drug marketplace, including 4-methyl-N-ethylcathinone (4-MEC) and 4-methyl-α-pyrrolidinopropiophenone (4-MePPP). Here we characterized the interactions of 4-MEC and 4-MePPP with transporters for 5-HT (SERT) and dopamine (DAT) using molecular, cellular and whole animal methods. In vitro transporter assays revealed that 4-MEC displays unusual 'hybrid' activity as a SERT substrate (i.e., 5-HT releaser) and DAT blocker, whereas 4-MePPP is a blocker at both transporters but more potent at DAT. In vivo microdialysis experiments in rat brain demonstrated that 4-MEC (1-3 mg/kg, i.v.) produced large increases in extracellular 5-HT, small increases in dopamine, and minimal motor stimulation. By contrast, 4-MePPP (1-3 mg/kg, i.v.) produced selective increases in dopamine and robust motor stimulation. Consistent with its activity as a SERT substrate, 4-MEC evoked inward current in SERT-expressing Xenopus oocytes, while 4-MePPP was inactive in this regard. To examine drug-transporter interactions at the molecular level, we modeled the fit of 4-MEC and 4-MePPP into the binding pockets for DAT and SERT. Subtle distinctions in ligand-transporter binding were found that account for the differential effects of 4-MEC and 4-MePPP at SERT. Collectively, our results provide key information about the pharmacology of newly-emerging mephedrone analogs, and give clues to structural requirements that govern drug selectivity at DAT versus SERT.Neuropsychopharmacology accepted article preview online, 15 December 2014. doi:10.1038/npp.2014.325.

Number of pages:1331
Date of publication:2015
Journal title:Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Peer reviewed:true
Digital Object Identifier (DOI):http://dx.doi.org/10.1038/npp.2014.325
Publication Type:Article