- Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters
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Background and Purpose: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. Experimental Approach: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3?mg·kg?1) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. Key Results: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. Conclusions and Implications: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood–brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.
- Mayer,Wimmer,Dillon-Carter,Partilla,Burchardt,Mihovilovic,Baumann,Sitte
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supporting information
p. 2657 - 2668
(2016/10/19)
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- 5-Aryl-imidazolin-2-ones as a scaffold for potent antioxidant and memory-improving activity
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A series of 5-phenyl-substituted-N-alkyl-imidazolin-2-ones with potent radical-scavenging activity and lipid peroxidation inhibitory activity was synthesized. Many of the compounds showed memory-improving effect in animal models independent of the inhibitory activity on lipid peroxidation.
- Watanabe, Kazutoshi,Morinaka, Yasuhiro,Hayashi, Yoshio,Shinoda, Masaki,Nishi, Hiroyoshi,Fukushima, Nobuko,Watanabe, Toshiaki,Ishibashi, Akira,Yuki, Satoshi,Tanaka, Masahiko
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p. 1478 - 1483
(2008/09/18)
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- MAO inhibition by arylisopropylamines: The effect of oxygen substituents at the β-position
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Twenty-nine arylisopropylamines, substituted at the β-position of their side chain by an oxo, hydroxy, or methoxy group, were evaluated in vitro as MAO-A and MAO-B inhibitors. The oxo derivatives ('cathinones') were in general less active as MAO-A inhibitors than the corresponding arylisopropylamines, but exhibited an interesting MAO-B inhibiting activity, which was absent in the hydroxy, methoxy, and β-unsubstituted analogues. These results suggest that selective affinity for the two MAO isoforms in this family of compounds is modulated not only by the aryl substitution pattern but also by the side-chain substituents on the arylalkylamine scaffold.
- Osorio-Olivares, Mauricio,Rezende, Marcos Caroli,Sepulveda-Boza, Silvia,Cassels, Bruce K.,Fierro, Angelica
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p. 4055 - 4066
(2007/10/03)
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