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
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Binding, Competitive
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Bromine / metabolism
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Carrier Proteins / metabolism*
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Chromatography, High Pressure Liquid
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Cocaine / analogs & derivatives
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Cocaine / metabolism
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Dopamine / metabolism*
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Dopamine Plasma Membrane Transport Proteins
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Fluoxetine / analogs & derivatives
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Fluoxetine / metabolism
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In Vitro Techniques
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Magnetic Resonance Spectroscopy
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Male
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins*
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Methylphenidate / analogs & derivatives
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Methylphenidate / metabolism*
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Methylphenidate / pharmacology
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Mice
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Microdialysis
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Motor Activity / drug effects
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Nerve Tissue Proteins / metabolism
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Norepinephrine / antagonists & inhibitors*
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Paroxetine / metabolism
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Serotonin Plasma Membrane Transport Proteins
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Structure-Activity Relationship
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Tomography, Emission-Computed, Single-Photon
Substances
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Carrier Proteins
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Dopamine Plasma Membrane Transport Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Serotonin Plasma Membrane Transport Proteins
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Slc6a4 protein, mouse
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Slc6a4 protein, rat
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Fluoxetine
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nisoxetine
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Methylphenidate
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Paroxetine
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(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
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Cocaine
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Bromine
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Dopamine
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Norepinephrine