Syntheses of novel diphenyl piperazine derivatives and their activities as inhibitors of dopamine uptake in the central nervous system.
A new series of diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, which were modified at sites between the diphenyl and piperazine moieties, was prepared and evaluated for dopamine transporter binding affinity with [(3)H]GBR12935 in rat striatal membranes. These synthesized compounds showed apparent dopamine transporter binding affinities (IC(50)<30 nM) and some of them were approximately equivalent in activity to GBR12909 known as a potent dopamine uptake inhibitor, showing the activities with IC(50) values of nanomolar range. Among them, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 2 was evaluated for extracellular dopamine levels in rat striatum using in vivo brain microdialysis. The intraperitoneal administration of 2 (0.01, 0.03, or 0.1 mmol/kg) induced dose-dependent increases of dopamine levels in rat striatal dialysates. The maximum increases in dopamine levels induced by 2 were greater than those by GBR12909. The pharmacological data of these novel diphenyl piperazine derivatives show that the compounds have potent dopamine uptake inhibitory activities in the central nervous system.
Kimura
Makoto
M
POLA Chemical Industries, Inc., Pharmaceutical R&D Laboratories, 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa 244-0812, Japan. t-namiki@pola.co.jp
Masuda
Tomoko
T
Yamada
Koji
K
Mitani
Masaki
M
Kubota
Nobuo
N
Kawakatsu
Nobuyuki
N
Kishii
Kenichi
K
Inazu
Masato
M
Kiuchi
Yuji
Y
Oguchi
Katsuji
K
Namiki
Takayuki
T
D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar
C461261:(1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate); 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