Add time:09/05/2019         Source:sciencedirect.com

1,4-Disubstituted piperazines such as GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxyl]ethyl]-4-(3-phenylpropyl)piperazine)and GBR 12935 (1-[2-[bis(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine) are among the most potent and selective ligands for the dopamine transporter in brain. However, they also bind to a widely distributed “piperazine acceptor site”. In order to assess whether the piperazine moiety of GBR 12909 is critical for binding to the dopamine transporter, two piperidine analogs of GBR 12909, one with the nitrogen proximal to the diphenylmethyloxy moiety (O-549, (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperidine), the other distal to this moiety (O-526, 4[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine) were synthesized. The affinities of O-526, O-549 and GBR 12909 for the dopamine and serotonin transporters in monkey caudate-putamen (Macaca fascicularis) were evaluated using [3H]WIN 35,428 ([3H]CFT, ([3HCFT, 2β-carbomethoxy-3β-4-(fluorophenyl)tropane) or [3H]GBR 12935 and [3H]citalopram to label the dopamine and serotonin transporters, respectively. O-526 inhibited [3H]WIN 35,428 binding with potencies that were similar to GBR 12909 (IC50: 24.9 ± 3.23 vs. 22.0 ± 2.2 nM, respectively) whereas O-549 was 24 times less potent than O-526 (IC50: 595 ± 148 nM). the selectivity of GBR 12909 for the dopamine over the serotonin transporter was retained by O-526 but not by O-549 which was relatively non-selective. These results indicate that only one of the two nitrogens on the basic GBR structure is needed for high affinity binding to the dopamine transporter. Moreover, the position of the nitrogen is crucial for determining not only affinity for the dopamine transporter, but als selectivity for the dopamine over the serotonin transporter. Using assay conditions in rodent striatum favorable for labeling of the “piperazine acceptor site”, O-526 displayed a lower affinity for the “piperazine acceptor site” (IC50: 404 ± 74) than did GBR 12909 (IC50: 37 ± 3). The results indicate that piperidine analogs of GBR 12909 may be suitable probes for the dopamine transporter.

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