| 12927856 |
Kimura M, Masuda T, Yamada K, Mitani M, Kubota N, Kawakatsu N, Kishii K, Inazu M, Kiuchi Y, Oguchi K, Namiki T: Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter. Bioorg Med Chem. 2003 Sep 1;11(18):3953-63.
The novel diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, including 1-[4,4-bis (4-fluorophenyl) butyl]-4-[2-hydroxy-3-(phenylamino) propyl] pipera zine 1, which were modified at the connective between the diphenyl and piperazine moieties, have been found to be potent dopamine uptake inhibitors. To study the further structure-activity relationship (SAR) of these compounds, a new series was synthesized, with modifications at the 2-hydroxy-3-phenylaminopropyl moiety of 1. The series was evaluated for dopamine transporter (DAT) binding affinity with [3H] GBR12935 in rat striatal membranes. Most of the compounds showed moderate to high DAT binding affinities and some were approximately equivalent in activity to compound 1 or GBR12909 as a dopamine uptake inhibitor, with IC (50) values of nanomolar range. The SAR suggested that on exhibiting a potent interaction with the DAT, there is probably a steric limitation around the benzene ring of the phenylamino moiety of 1, allowing only small-sized substituents with the exception of basic moieties at the 4-position. In addition, the SAR at the 3-amino-2-propanol moiety of 1 suggested that either the nitrogen atom with an electron donating substituent or the unsubstituted nitrogen atom and also the hydroxy group are desirable for elicitation of a potent DAT binding affinity. |
82(1,1,1,2) |