Perry E K, Smith C J, Court J A, Bonham J R, Rodway M, Atack J R
Department of Neuropathology, Newcastle General Hospital, Newcastle upon Tyne, U.K.
Neurosci Lett. 1988 Aug 31;91(2):211-6. doi: 10.1016/0304-3940(88)90770-7.
Tetrahydroaminoacridine (THA) has recently been reported to be more useful in the treatment of Alzheimer's disease than physostigmine. A comparison of the effects of these two anticholinesterase agents on in vitro enzyme and receptor activities of human cerebral cortex (obtained at autopsy) revealed similarities in their interactions with acetylcholinesterase (AChE) but striking differences in their ability to displace both nicotinic and muscarinic radioligands from membrane preparations. IC50 values (the concentration required to reduce enzyme activity by 50%) for the inhibition of total tissue AChE were 7.9 x 10(-7) M and 4.5 x 10(-8) M for THA and physostigmine, respectively, and similar values were also obtained for individual molecular forms of AChE (monomer G1, dimer G2 and tetramer G4) separated by sucrose density gradient centrifugation. In contrast, IC50 values for [3H]nicotine displacement (a measure of nicotinic cholinergic receptor binding) differed 1000-fold for THA (2 x 10(-5) M) and physostigmine (2 x 10(-2) M) and 100-fold for [3H]N-methylscopolamine displacement (a measure of muscarinic cholinergic receptor binding). Differences were also noted in the inhibition of carbachol stimulated polyphosphoinositide (PI) hydrolysis (a measure of muscarinic receptor induced second messenger activity) in isolated rat cortical miniprisms. It is suggested that variations in clinical efficacy of THA and physostigmine may be related less to their anticholinesterase properties and more to their interactions with other activities such as cholinergic receptors.
据最近报道，四氢氨基吖啶（THA）在治疗阿尔茨海默病方面比毒扁豆碱更有效。比较这两种抗胆碱酯酶药物对人大脑皮质（尸检获得）体外酶活性和受体活性的影响发现，它们与乙酰胆碱酯酶（AChE）的相互作用相似，但在从膜制剂中置换烟碱和毒蕈碱放射性配体的能力方面存在显著差异。THA和毒扁豆碱抑制总组织AChE的IC50值（使酶活性降低50%所需的浓度）分别为7.9×10⁻⁷M和4.5×10⁻⁸M，通过蔗糖密度梯度离心分离的AChE的各个分子形式（单体G1、二聚体G2和四聚体G4）也得到了类似的值。相比之下，THA（2×10⁻⁵M）和毒扁豆碱（2×10⁻²M）的[³H]尼古丁置换的IC50值相差1000倍，[³H]N-甲基东莨菪碱置换（毒蕈碱胆碱能受体结合的一种测量方法）的IC50值相差100倍。在分离的大鼠皮质小块中，对卡巴胆碱刺激的多磷酸肌醇（PI）水解（毒蕈碱受体诱导的第二信使活性的一种测量方法）的抑制也存在差异。有人提出，THA和毒扁豆碱临床疗效的差异可能与其抗胆碱酯酶特性关系较小，而与其与其他活性如胆碱能受体的相互作用关系较大。
