Design, synthesis, and characterization of a novel, 4-[2-(diphenylmethoxy)ethyl]-1-benzyl piperidine-based, dopamine transporter photoaffinity label

The dopamine transporter (DAT) has been implicated strongly in cocaine's re inforcing effects. Many derivatives of piperidine analogs of GBR 12909 have been developed and were found to be quite potent and selective for the DAT . In this regard, most of these derivatives were found to be much more sele ctive for the DAT than conventional GBR compounds e.g. GBR 12909 when their selectivity was compared with the serotonin transporter (SERT). A brief st ructure-activity relationship (SAR) study has been carried out in the devel opment of a novel photoaffinity ligand which illustrated the effect of the presence of a sterically bulky iodine atom next to the azido group in activ ity and selectivity for the DAT. This SAR study also led to the development of the compound 4 which is one of the most potent and selective blockers f or the DAT known today. The photoaffinity ligand [I-125]AD-96-129 was incor porated into the DAT molecule as was demonstrated by immunoprecipitation wi th serum 16 which is specific for DAT. This photolabeling was antagonized b y DAT-specific blockers and was unaffected by specific SERT and norepinephr ine transporter (NET) blockers indicating interaction of this novel ligand with the DAT. (C) 2001 Elsevier Science Inc. All rights reserved.