Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-2-Bis(4-fluorophenyl)methoxyethyl-4-(3-phenylpropyl)piperazine and 1-2-(Diphenylmethoxy)ethyl-4-(3-phenylpropyl)piperazine: Role of Amino Fluoro Hydroxyl Methoxyl Methyl Methylene and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

摘要

In our search for potential cocaine-abuse therapeutic agents, novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909, >1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, >2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were designed, synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). The affinities of these ligands for DAT and SERT were controlled by the position of the substituents and their electronic and steric effects. This information could help us better understand and predict the influence of structural modification, and to discover new high-affinity DAT ligands possessing a range of affinities for SERT. The C2 series showed a quite different structure-activity relationship from the C3 series. 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. 2-Fluoro-substituted analogs (S)->10 and (R)->10 displayed substantial enantioselectivity in transporter affinity. In the series, (S)->10 had the highest DAT binding affinity and good DAT selectivity. The 2-amino-substituted (R)->8 showed the highest SERT binding affinity in this series and essentially the same affinity for DAT (Ki = 22 and 20 nM, respectively). Thus, (R)->8 might be a lead for the discovery of a dual-action transporter ligand able to simultaneously block DAT and SERT. Compounds >16 and >18, the oxygenated derivatives of >2, possessed the best selectivity for DAT (SERT/DAT ratio = 254 and 250, respectively).