Binding of bromine-substituted analogs of methylphenidate to monoamine transporters

Eur J Pharmacol. 1994 Oct 24;264(2):177-82. doi: 10.1016/0014-2999(94)00460-9.

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]2 beta-carbomethoxy-3 beta-(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 > or = 1 microM) 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Bromine / metabolism
  • Carrier Proteins / metabolism*
  • Chromatography, High Pressure Liquid
  • Cocaine / analogs & derivatives
  • Cocaine / metabolism
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / metabolism
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Methylphenidate / analogs & derivatives
  • Methylphenidate / metabolism*
  • Methylphenidate / pharmacology
  • Mice
  • Microdialysis
  • Motor Activity / drug effects
  • Nerve Tissue Proteins / metabolism
  • Norepinephrine / antagonists & inhibitors*
  • Paroxetine / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship
  • Tomography, Emission-Computed, Single-Photon

Substances

  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Slc6a4 protein, rat
  • Fluoxetine
  • nisoxetine
  • Methylphenidate
  • Paroxetine
  • (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
  • Cocaine
  • Bromine
  • Dopamine
  • Norepinephrine