Structural significance of azaheterocyclic amines related to Parkinson's disease for dopamine transporter.
We have evaluated the neuronal uptake of 12 neutral and quaternary azaheterocyclic amines that are possible candidates for idiopathic Parkinson's disease via dopamine transporter of striatal synaptosomes. The double-reciprocal plots for dopamine transporter obtained from Wistar rat and C57BL/6 mouse synaptosomes with N-methyl-4-phenylpyridinium cation (MPP+) as a substrate were identical to each other. Neutral beta-carbolines and tetrahydroisoquinolines were unfavorable substrates for dopamine transporter. The quarternization of these compounds strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Although catechol tetrahydroisoquinolines were weak substrates, their quarternization reduced their original properties as substrates for dopamine transporter. These results provide both topographic and electrogenic information of azaheterocyclic amines for the dopamine transporter-mediated influx. The intramolecular distance between the N-atom and the centroid of the benzene ring could be an important factor for the recognition of binding site of dopamine transporter, and an adequate net charge similar to dopamine would be further required for translocation into the cells.
Matsubara
K
K
Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical College, Japan.
Senda
T
T
Uezono
T
T
Fukushima
S
S
Ohta
S
S
Igarashi
K
K
Naoi
M
M
Yamashita
Y
Y
Ohtaki
K
K
Hayase
N
N
Akutsu
S
S
Kimura
K
K
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009498:Neurotoxins / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D002352:Carrier Proteins; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D006571:Heterocyclic Compounds; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine