The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem. In our program to develop treatment medications, we synthesized novel derivatives of 1-2-bis(4-fluorophenyl)methoxyethyl-4-(3-phenylpropyl)piperazine (GBR 12909) and 1-2-(diphenylmethoxy)ethyl-4-(3-phenylpropyl)piperazine (GBR 12935) with various substituents in positions C2 and C3 of the phenylpropyl side chain. These compounds were evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp2 hybridized substituents had a detrimental effect on affinity for DAT. The oxygenated derivatives possessed the best selectivity for DAT. ? ? Lastly, we published a review on the structure-activity relationships of biogenic amine reuptake inhibitors related to GBR 12909 as potential cocaine and methamphetamine treatment agents.
| Hsin, Ling-Wei; Chang, Li-Te; Rothman, Richard B et al. (2008) Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: role of amino, fluoro, hydroxyl, methoxyl, methyl, m J Med Chem 51:2795-806 |
