Binding of bromine-substituted analogs of methylphenidate to monoamine transporters

Dongfeng Pan, S. John Gatley, Stephen L. Dewey, Ruoyan Chen, David A. Alexoff, Yu Shin Ding, Joanna S. Fowler

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

We synthesized the o-, m- and p-bromo derivatives of dl-threo-methylphenidate from the corresponding bromophenylacetonitriles by modification of the literature synthesis of methylphenidate (Panizzon, Helv. Chim. Acta 1944, 27, 1748). In in vitro binding assays all three dl-threo bromo compounds had higher affinities than methylphenidate for dopamine transporter sites labeled with [3H]2β-carbomethoxy-3β-(4-fluorophenyl)tropane ([3H]WIN 35,428; IC50 = 13, 4, 20 and 82 nM for o-, m-, and p-bromo compounds, and unsubstituted methylphenidate, respectively). They also bound more strongly than methylphenidate to norepinephrine reuptake sites labeled with [3H]nisoxetine (IC50 = 32, 20, 31 and 440 nM, respectively), but were weak ligands (IC50 ≥ 1 μM) at the serotonin transporter labeled with [3H]paroxetine. In addition, the bromine substituted derivatives demonstrated similar activity to methylphenidate in vivo in rodents in terms of inhibition of heart uptake of [3H](-)-norepinephrine, elevation of striatal extracellular dopamine, and stimulation of locomotor activity.

Original languageEnglish
Pages (from-to)177-182
Number of pages6
JournalEuropean Journal of Pharmacology
Volume264
Issue number2
DOIs
StatePublished - 24 Oct 1994
Externally publishedYes

Keywords

  • Dopamine transporter
  • Locomotor activity
  • Methylphenidate
  • Microdialysis
  • Norepinephrine transporter
  • dl-threo-Methylphenidate

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