Synthesis and transporter binding properties of bridged piperazine analogues of 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909)

A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpr opyl)piperazine (2) and 1-{2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenyl propyl)piperazine (3)(GBR 12935 and GBR 12909, respectively), in which;the piperazine moiety was replaced by bridged piperazines for structural rigidi ty,has been designed, synthesized, and evaluated for their ability to bind to the dopamine transporter;(DAT) and to inhibit the uptake of H-3-labeled dopamine (DA), The binding data indicated that compounds 7 and Il, the N-me thyl- and N-propylphenyl-3,8-diaza[3.2.1]bicyclooctane analogues of 3, show ed high affinity for the DAT (IC50 = 8.0 and 8.2 nM, respectively), and 7 h ad,high selectivity at the DAT relative to the serotonin transported (SERT) (88- and 93-fold for binding and reuptake, respectively). They also displa yed linear activity in DA uptake inhibition, possessing a similar binding a nd reuptake inhibition profile to 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 II. Interestingly, this c ompound exhibited a high ratio (29-fold) of IC50 for the inhibition of DA r euptake versus binding to the DAT.; Replacing the piperazine moiety of 2 an d 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-diaza bicyclo [4.2.1]nonane gave compounds 28-33. However, the binding data showe d that compound 32 displayed a 10-fold decrease in affinity at the DAT and a 100-fold decrease in selectivity at the DAT relative to the SERT compared to its corresponding homopiperazine compound 4.