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

[摘要]：(Heterocyclic Compounds (More Than One Hetero Atom)) Section Novel derivs. of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) and with various substituents in positions C2 and C3 of the phenylpropyl side chain, e.g. I (R1 = Ph, 4-FC6H4; R2 = H, F, OH, Me, MeO, NH2; R3 = R5 = H; R4 = H, OH), were synthesized and 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. In the series, the 2-fluoro-substituted (S)-I (R1 = 4-FC6H4; R2 = F; R3 = R4 = R5 = H) had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-I (R1 = 4-FC6H4; R2 = NH2; R3 = R4 = R5 = H) showed essentially the same affinity for DAT and SERT. The oxygenated derivs. I (R1 = Ph; R2R3 = O; R4 = R5 = H) and I (R1 = Ph; R2 = R3 = H; R4 = OH; R5 = Me) possessed the best selectivity for DAT.

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