Tetrahydropapaveroline and its derivatives inhibit dopamine uptake through dopamine transporter expressed in HEK293 cells.
Tetrahydropapaveroline (THP), an isoquinoline alkaloid, has been detected in brain and urine of Parkinsonian patients on L-dopa medication, and in the urine and brain of rats after L-dopa or acute ethanol administration. Since THP is considered to be synthesized from dopamine, it may affect dopaminergic neurons through the reuptake system, i.e. dopamine transporter (DAT). To determine whether THP has affinity for DAT, we generated a cell line which stably expresses DAT and examined whether THP and its derivatives could inhibit [3H]DA uptake in these cells. Ki of THP and three derivatives (1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), 1-(3',4'-dibydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3',4' DHBnTIQ) and 6,7-dihydroxy-1-benzyl-1,2,3,4-tetrahydroisoquinoline (6,7 DHBnTIQ)) for inhibition of [3H]DA uptake were about 41, 35, 23 and 93 microM, respectively, which were similar to the Ki of 1-methyl-4-phenylpyridinium ion (MPP+) (28 microM). These results suggest that THP and its derivatives might be uptaken through DAT and be involved in Parkinson's disease and/or alcohol addiction.
Okada
T
T
Division of Tracer Kinetics, Biomedical Research Center, Osaka University Medical School, Suita, Japan. tokada@anat2.med.osaka-u.ac.jp
Shimada
S
S
Sato
K
K
Kotake
Y
Y
Kawai
H
H
Ohta
S
S
Tohyama
M
M
Nishimura
T
T
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013329:Structure-Activity Relationship; D013765:Tetrahydropapaveroline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014162:Transfection
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C493214:SLC6A3 protein, human; C493216:Slc6a3 protein, rat; D013765:Tetrahydropapaveroline; D004298:Dopamine