| Abstract
| - A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2)and 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (3) (GBR 12935 andGBR 12909, respectively), in which the piperazine moiety was replaced by bridged piperazinesfor structural rigidity, has been designed, synthesized, and evaluated for their ability to bindto the dopamine transporter (DAT) and to inhibit the uptake of 3H-labeled dopamine (DA).The binding data indicated that compounds 7 and 11, the N-methyl- and N-propylphenyl-3,8-diaza[3.2.1]bicyclooctane analogues of 3, showed high affinity for the DAT (IC50 = 8.0 and 8.2nM, respectively), and 7 had high selectivity at the DAT relative to the serotonin transporter(SERT) (88- and 93-fold for binding and reuptake, respectively). They also displayed linearactivity in DA uptake inhibition, possessing a similar binding and reuptake inhibition profileto 3. The N-indolylmethyl analogue 16 showed the highest affinity (IC50 = 1.4 nM) of the series,with a 6-fold increase over its corresponding N-phenypropyl derivative 11. Interestingly, thiscompound exhibited a high ratio (29-fold) of IC50 for the inhibition of DA reuptake versus bindingto the DAT. Replacing the piperazine moiety of 2 and 3 with (1S,4S)-2,5-diazabicyclo[2.2.1]heptane resulted in compounds 23−26, which showed moderate to poor affinity (IC50 = 127−1170 nM) for the DAT. Substitution of the homopiperazine moiety of 4 with a more rigid 3,9-diazabicyclo[4.2.1]nonane gave compounds 28−33. However, the binding data showed thatcompound 32 displayed a 10-fold decrease in affinity at the DAT and a 100-fold decrease inselectivity at the DAT relative to the SERT compared to its corresponding homopiperazinecompound 4.
|
