N-methyl amine-substituted fluoxetine derivatives: new dopamine transporter inhibitors.
Transport of dopamine (DA) by the dopamine transporter from the synaptic cleft into the presynaptic terminals plays a key role in terminating dopaminergic neurotransmission. The binding of psychostimulants to their recognition sites on the DA transporter leads to an inhibition of DA transport and a subsequent rising of the dopamine contents in the synaptic cleft is ascribed to a mode of psychostimulation. Discovery of dopamine transporter inhibitors would be useful with regard to substituting for cocaine and minimizing its abuse. Recently, a number of fluoxetine analogues were synthesized, especially focusing on the substitution of N-methyl amine group through modifying the structure of the fluoxetine, N-methyl-3-[p-trifluoromethylphenoxy]-3-phenylpropylamine, widely used as an antidepressant. Among them, the pharmacological properties of FD-2, (R)-N-ethanol-3-(4-trifluorophenoxy)-3-phenyl propaneamine and FD-4, N-(R)-3-trifluorophenoxy-3-phenylpropane-imidazole with a higher affinity for the DA transporter were characterized in terms of dopamine transporter inhibition expecting for useful cocaine substitutes. Effects of the compounds on [H(3)]dopamine uptake, [I(125)]RTI-55 binding, and DA transporter-associated currents were examined with the ligand binding assays and voltage clamping technique in human embryonic kidney (HEK)-293 cells where the recombinant human DA transporter (hDAT) was stably expressed. Our results showed that (i) fluoxetine was potent in inhibiting both the uptake of [H(3)]DA (IC(50) = 0.21 +/- 0.032 mM, n = 3) and the [I(125)]RTI-55 binding (IC(50) = 0.23 +/- 0.012 mM, n = 10); (ii) N-methyl amine substituted fluoxetine analogues, FD-2 and FD-4 were equally or more potent than fluoxetine itself in terms of inhibition of [H(3)]DA uptake (IC50 FD-2: 0.077 +/- 0.0032 mM (n = 3); FD-4: 0.26 +/- 0.13 mM (n = 3), inhibition of [I(125)]RTI-55 binding, and reduction in DA transporter-associated currents, suggesting that these analogues could be a new class of dopamine transporter inhibitors.
Yoon
Young Sil
YS
Department of Biological Sciences, Ajou University, Suwon, 443-749, Korea.
Cho
Taesup
T
Yoon
Sung-Hwa
SH
Min
Churl Ki
CK
Lee
Changho
C
D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002460:Cell Line; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D004594:Electrophysiology; D004983:Ethanolamines / Q000494:pharmacology*; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000494:pharmacology*; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D018687:Antidepressive Agents, Second-Generation; D050483:Dopamine Plasma Membrane Transport Proteins; D004983:Ethanolamines; D007093:Imidazoles; C549414:N-3-trifluorophenoxy-3-phenylpropaneimidazole; C549413:N-ethanol-3-(4-trifluorophenoxy)-3-phenylpropaneamine; D010647:Phenyl Ethers; D011994:Recombinant Proteins; D005473:Fluoxetine; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine; D004298:Dopamine