Binding of bromine-substituted analogs of methylphenidate to monoamine transporters.
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.
Pan
D
D
Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973.
Gatley
S J
SJ
Dewey
S L
SL
Chen
R
R
Alexoff
D A
DA
Ding
Y S
YS
Fowler
J S
JS
D000818:Animals; D001667:Binding, Competitive; D001966:Bromine / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008774:Methylphenidate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D017374:Paroxetine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D005473:Fluoxetine; C011386:nisoxetine; D008774:Methylphenidate; D017374:Paroxetine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D001966:Bromine; D004298:Dopamine; D009638:Norepinephrine