Potent and selective ligands for the dopamine transporter (DAT): structure-activity relationship studies of novel 4-[2-(diphenylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine analogues.
Molecular structural modifications of 4-[2-(diphenylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine (1a), a dopamine transporter (DAT)-specific ligand, generated several novel analogues. Biological activities of these new molecules for their binding to the DAT and serotonin transporter (SERT) were evaluated in rat striatal membranes. Some of these new analogues were more potent and selective than GBR 12909 when their binding to the DAT relative to SERT was compared. Thus compounds 9 and 19a were among the most potent (IC50 = 6.6 and 6.0 nM, respectively) and selective (DAT/SERT = 33.8 and 30.0, respectively) compounds in this series, and they were more active than GBR 12909 (IC50 = 14 nM, DAT/SERT = 6.1). Introduction of a double bond in the N-propyl side chain of these molecules did not influence their activities to a great extent. Bioisosteric replacement of the aromatic phenyl group by a thiophene moiety produced some of the most potent compounds in this series.
Dutta
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AK
Organix Inc., Woburn, Massachusetts 01801, USA.
Coffey
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LL
Reith
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ME
D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003042:Cocaine / Q000037:antagonists & inhibitors; D003342:Corpus Striatum / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C111313:4-(2-((2-thienyl)phenylmethoxy)ethyl)-1-(3-phenylpropyl)piperidine; C111312:4-(2-(diphenylmethoxy)ethyl)-1-(3-(4'-fluorophenyl)propyl)piperidine; D001559:Benzhydryl Compounds; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D010880:Piperidines; C493216:Slc6a3 protein, rat; C043425:vanoxerine; D003042:Cocaine