Manetti D, Ghelardini C, Bartolini A, Dei S, Galeotti N, Gualtieri F, Romanelli M N, Teodori E
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy.
J Med Chem. 2000 Nov 16;43(23):4499-507. doi: 10.1021/jm000972h.
Several 4-substituted 1-acylpiperazines, obtained by molecular simplification of 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones, have been synthesized and tested in vivo on the mouse passive avoidance test, to evaluate their nootropic activity. The results show that, apparently, an N-acylpiperazine group can mimic the 2-pyrrolidinone ring of 1,4-diazabicyclo[4.3.0]nonan-9-one, as the compounds of the new series maintain high nootropic activity. Moreover molecular simplification produces more clear-cut structure-activity relationships with respect to the parent series. The mechanism of action also appears to be similar in the two series. In fact, although the molecular mechanism remains to be elucidated, the most potent compound of each class (DM232 and 13, DM235) is able to increase acetylcholine release in rat brain. Piperazine derivatives represent a new class of nootropic drugs with an in vivo pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference compound. Among the compounds studied, 13 (DM235) shows outstanding potency, being active at a dose of 0.001 mg kg(-1) sc.
通过对4-取代的1,4-二氮杂双环[4.3.0]壬烷-9-酮进行分子简化得到了几种4-取代的1-酰基哌嗪，并在小鼠被动回避试验中进行了体内测试，以评估它们的益智活性。结果表明，显然，N-酰基哌嗪基团可以模拟1,4-二氮杂双环[4.3.0]壬烷-9-酮的2-吡咯烷酮环，因为新系列的化合物保持了较高的益智活性。此外，相对于母体系列，分子简化产生了更明确的构效关系。两个系列的作用机制似乎也相似。事实上，尽管分子机制仍有待阐明，但每类中最有效的化合物（DM232和13、DM235）都能够增加大鼠脑中乙酰胆碱的释放。哌嗪衍生物代表了一类新的益智药物，其体内药理学特征与吡拉西坦非常相似，相对于参比化合物显示出更高的效力。在所研究的化合物中，13（DM235）显示出卓越的效力，皮下注射剂量为0.001 mg kg(-1)时具有活性。
