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目的:合成以他克林(THA)为原药的化学传输系统,证实其有脑靶向性。方法:将THA与氯乙酰氯连接,再与烟酰胺成季胺盐,最后将其还原成二氢吡啶载体介导的前体药物。结果:用NMR,MS等方法对前药进行结构表征鉴定。前药分子脂溶性比THA大,体内外实验各组织药物浓度监测显示脑组织匀浆浓度高于其他组织匀浆。结论:合成的二氢吡啶载体介导的前体药物脑内药物浓度高于外周,预示着有良好的脑靶向性。
OBJECTIVE: To synthesize a chemical delivery system using tacrine (THA) as the original drug and to confirm its brain targeting. METHODS: THA was coupled with chloroacetyl chloride and then to nicotinamide as a quaternary ammonium salt, which was then reduced to dihydropyridine carrier-mediated prodrugs. Results: The structures of the prodrugs were identified by NMR, MS and other methods. The pro-drug molecules were more fat-soluble than THA, and monitoring of drug concentrations in various tissues in vivo and in vitro showed that the concentration of brain homogenates was higher than that of other tissue homogenates. CONCLUSIONS: The synthetic dihydropyridine-mediated prodrug brain concentration is higher than that of the periphery, indicating good brain targeting.