title: Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter.
abstract: 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]piperazine 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.
authors.affiliation: POLA Chemical Industries, Inc., Pharmaceutical R&D Laboratories, 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa 244-0812, Japan. m-kimura@pola.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Kimura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Masuda
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Masaki
authors.initials: M
authors.lastname: Mitani
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kubota
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kawakatsu
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kishii
authors.forename: Masato
authors.initials: M
authors.lastname: Inazu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kiuchi
authors.forename: Katsuji
authors.initials: K
authors.lastname: Oguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Namiki
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000737:chemistry*; D002462:Cell Membrane / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493216:Slc6a3 protein, rat; C043425:vanoxerine; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine