Abstract
We previously reported that the psychostimulant drug methcathinone inhibits
monoamine neurotransmitter accumulation into human platelets and cultured cells
expressing the human biogenic amine uptake transporters. By structural analogy
to known phenylalkylamine substrates for the serotonin transporter (SERT), we
hypothesized that methcathinone is also a substrate for the SERT and that
inhibition of serotonin uptake by methcathinone occurs through competition for
the substrate binding site within the SERT. To test our hypothesis, [3H]methcathinone was synthesized from phenylpropanolamine
in two steps and purified by preparative TLC followed by HPLC. We then tested
whether [3H]methcathinone was taken up by
transfected cells expressing the human SERT (293SERT) or by wild-type HEK 293
cells. In support of our hypothesis, when increasing concentrations of [3H]methcathinone
were incubated with 293SERT cells under conditions used to assess biogenic
amine transport, saturable, single site accumulation
of radiolabel was observed. The uptake of [3H]methcathinone
was temperature, inhibitor, and sodium-sensitive, and was not observed in
wild-type HEK 293 cells. These results demonstrate that the SERT is relatively
indiscriminate with respect to the chemical structure of transported molecules
and suggests that inhibition of serotonin uptake by methcathinone most likely
occurs through simple competition for the serotonin binding site in the SERT.
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