Structure-activity relationship studies of highly selective inhibitors of the dopamine transporter: N-benzylpiperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.
A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl-1-benzylpiperidines were examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Binding results indicated that the presence of an electron-withdrawing group in the C(4)-position of the N-benzyl group is beneficial for binding to the DAT. Several analogues have been identified with high affinity for the DAT, up to 500-fold selectivity over the SERT and about 170-fold selectivity over the NET in binding and uptake inhibition assays.
Greiner
Elisabeth
E
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland 20892, USA.
Prisinzano
Thomas
T
Johnson
Edward M
EM
Dersch
Christina M
CM
Marcus
Jamila
J
Partilla
John S
JS
Rothman
Richard B
RB
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D002352:Carrier Proteins / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D010880:Piperidines; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D012701:Serotonin; C043425:vanoxerine; D004298:Dopamine; D009638:Norepinephrine