Matsubara K, Senda T, Uezono T, Fukushima S, Ohta S, Igarashi K, Naoi M, Yamashita Y, Ohtaki K, Hayase N, Akutsu S, Kimura K
Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical College, Japan.
Eur J Pharmacol. 1998 May 1;348(1):77-84. doi: 10.1016/s0014-2999(98)00131-9.
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.
我们通过纹状体突触体的多巴胺转运体评估了12种中性和季铵化氮杂环胺的神经元摄取情况，这些氮杂环胺可能是特发性帕金森病的潜在候选物。以N - 甲基 - 4 - 苯基吡啶阳离子（MPP +）为底物，从Wistar大鼠和C57BL / 6小鼠突触体获得的多巴胺转运体双倒数图彼此相同。中性β-咔啉和四氢异喹啉是多巴胺转运体的不利底物。这些化合物的季铵化显著增加了对多巴胺转运体的亲和力，其Km值比MPP +大2 - 10倍，Vmax值小10倍。虽然儿茶酚四氢异喹啉是弱底物，但其季铵化降低了它们作为多巴胺转运体底物的原有性质。这些结果提供了氮杂环胺通过多巴胺转运体介导的内流的拓扑和电生理信息。N原子与苯环质心之间的分子内距离可能是识别多巴胺转运体结合位点的重要因素，并且进一步需要与多巴胺相似的适当净电荷才能转运到细胞中。
