Tolerance in the replacement of the benzhydrylic O atom in 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives by an N atom: development of new-generation potent and selective N-analogue molecules for the dopamine transporter.
The replacement of the benzhydrylic oxygen atom of our previously developed dopamine transporter (DAT)-specific ligands 4-[2-(diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine, 1a, and 4-[2-(bis(4-fluorophenyl)methoxy)ethyl]-1-benzylpiperidine, 1b, by a nitrogen atom resulted in the development of the N-analogues 4-[2-((diphenylmethyl)amino)ethyl]-1-[(4-fluorophenyl)methyl]pi peridi ne, 4a, and 4-[2-((bis(4-fluorophenyl)methyl)amino)ethyl]-1-benzylpiperidine, 4b. Biological evaluation of these compounds in rat striatal tissue and in HEK-293 cells expressing the cloned human transporters demonstrated high potency and selectivity of these compounds for the DAT. Thus the potency of the compound 4a for the DAT was 9.4 and 30 nM in rat striatal tissue and in the cloned transporter cells, and its binding selectivity for the DAT compared to the serotonin transporter (SERT) for these two systems was 62 and 195, respectively. The compound 4b similarly exhibited high potency and selectivity for the DAT. Thus, the replacement of the O atom in 1a,b by an N atom in 4a,b only had small effects on potency and selectivity. In comparison with GBR 12909 [1-[2-(bis(4-fluorophenyl)methoxy)ethyl]-4-(3-phenylpropyl)piperazine ] and WIN 35,428 [3beta-(p-fluorophenyl)-2beta-carbomethoxytropane] binding, these two novel N-analogues were slightly more potent and far more selective for the DAT. Thus, these novel N-analogues represent more polar new-generation piperidine congeners of GBR 12909. They might have useful potential application in developing a pharmacotherapy for cocaine dependence.
Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801, USA.
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D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D015283:Citalopram / Q000378:metabolism; D003001:Cloning, Molecular; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D014162:Transfection
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D010880:Piperidines; D011994:Recombinant Proteins; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D015283:Citalopram; D012701:Serotonin; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine