Fleck Christian, Appenroth Dorothea, Fang Lei, Schott Yvonne, Lehmann Jochen, Decker Michael
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany.
Arzneimittelforschung. 2010;60(6):299-306. doi: 10.1055/s-0031-1296291.
Two tacrine-ferulic acid hybrids (1 A, 1 B) and three beta-carboline derivatives (BCs; 2A, 2B, 2C) were tested in vivo on 3-month-old female rats as multi-potent anti-Alzheimer drug candidates. In vitro, the two tacrine-ferulic acid hybrids show higher acetylcholinesterase (AChE) inhibitory activity and comparable butyrylcholinesterase (BChE) inhibitory activity compared to tacrine (CAS 1684-40-8). However, in vivo both substances have no beneficial effect on scopolamine (CAS 51-34-3) induced cognition impairment. On the contrary, 1B even worsen the scopolamine induced cognition impairment. The beta-carboline derivatives 2A, 2B, and 2 C, the inhibitory potency of which at AChE reaching tacrine activity does not antagonize scopolamine induced impairment of cognition in rats measured in radial maze paradigm. Compounds 2A and 1B might act as positive allosteric modulators of scopolamine action at the muscarinic acetylcholine receptors. On the basis of these results it can be concluded that both ferulic acid- (CAS 537-98-4) and BC-derivatives are not qualified as cognition improving drugs and further studies in this field should be focussed on other pharmaceutical leads to find effective anti-Alzheimer drugs.
两种他克林-阿魏酸杂合物（1A、1B）和三种β-咔啉衍生物（BCs；2A、2B、2C）作为多效抗阿尔茨海默病候选药物，在3月龄雌性大鼠体内进行了测试。在体外，与他克林（CAS 1684-40-8）相比，这两种他克林-阿魏酸杂合物显示出更高的乙酰胆碱酯酶（AChE）抑制活性以及相当的丁酰胆碱酯酶（BChE）抑制活性。然而，在体内，这两种物质对东莨菪碱（CAS 51-34-3）诱导的认知障碍均无有益作用。相反，1B甚至会加重东莨菪碱诱导的认知障碍。β-咔啉衍生物2A、2B和2C，其对AChE的抑制效力达到他克林的活性，但在放射状迷宫实验中测量时，它们并不能拮抗东莨菪碱诱导的大鼠认知障碍。化合物2A和1B可能作为东莨菪碱在毒蕈碱型乙酰胆碱受体上作用的正变构调节剂。基于这些结果，可以得出结论，阿魏酸（CAS 537-98-4）和BC衍生物均不符合作为改善认知药物的条件，该领域的进一步研究应集中在其他药物先导物上，以寻找有效的抗阿尔茨海默病药物。
