[3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel probes for the dopamine transporter.
In a continuing effort to identify novel probes with which to study the dopamine transporter (DAT), we discovered that the sigma receptor antagonist, rimcazole, binds with moderate affinity (K(i)=224nM) to the DAT. The results from previous SAR studies suggested that substitution of the carbazole ring system of rimcazole with bis-(4'-fluorophenyl)amine might improve binding affinity and selectivity for the DAT. Thus, a novel series of [3-cis-3,5-dimethyl-(1-piperazinyl)alkyl]bis-(4'-fluorophenyl)amines were synthesized. The most potent compound in this series (9b) displaced [3H]WIN 35,428 binding in rat caudate-putamen (K(i)=17.6nM) with comparable affinity to GBR 12909. Despite high-affinity binding at DAT, and structural similarity to GBR 12909, preliminary studies suggest 9b behaves more like rimcazole than GBR 12909 and does not demonstrate cocaine-like psychostimulant behavior in mice.
Cao
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Medicinal Chemistry Section, National Institute on Drug Abuse - Intramural Research Program, Baltimore, MD 21224, USA.
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Kopajtic
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Katz
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Newman
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D000818:Animals; D002227:Carbazoles / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D051381:Rats
D002227:Carbazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493216:Slc6a3 protein, rat; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C043425:vanoxerine; C034931:rimcazole; D003042:Cocaine