Chatterjee T K, Long J P, Cannon J G, Bhatnagar R K
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City 52242.
Eur J Pharmacol. 1988 May 10;149(3):241-8. doi: 10.1016/0014-2999(88)90654-1.
The potency of hemicholinium-3 (HC-3) and its analogs to inhibit sodium dependent high affinity choline uptake were evaluated in rat striatal synaptosomal preparation. Hemicholinium-3 inhibited sodium dependent high affinity choline uptake (IC50 = 18 nM) while the half molecule of HC-3, HC-15, was inactive. The order of potency for choline uptake inhibition of piperidine substituted HC-3 molecule was as follows: 4-methylpiperidine (A-5 and CA-5) much greater than HC-3 much greater than unsubstituted piperidines (CA-1 and A-1) much greater than 2- or 3-methylpiperidine (A-2 and A-3) and 4-hydroxypiperidine (A-7). The tertiary amine derivative of 4-methylpiperidine substituted HC-3 (A-4) was nearly 10-fold less potent than its corresponding quaternary derivative (A-5). Choline uptake was inhibited competitively by HC-3 and non-competitively by A-5. The inhibition of choline uptake by A-5 was readily reversible by washing. A-5 did not inhibit the uptake of dopamine and gamma-aminobutyric acid. These findings suggest that the N-methyl,4-methylpiperidine analog of HC-3 (A-5) is the most potent of all known inhibitors of sodium dependent high affinity choline uptake and that the inhibition of choline uptake by this compound is mediated through a mechanism distinct from a simple competitive one.
在大鼠纹状体突触体标本中评估了半胱氨酸-3（HC-3）及其类似物抑制钠依赖性高亲和力胆碱摄取的效力。半胱氨酸-3抑制钠依赖性高亲和力胆碱摄取（IC50 = 18 nM），而HC-3的半分子HC-15无活性。哌啶取代的HC-3分子对胆碱摄取抑制的效力顺序如下：4-甲基哌啶（A-5和CA-5）远大于HC-3远大于未取代的哌啶（CA-1和A-1）远大于2-或3-甲基哌啶（A-2和A-3）以及4-羟基哌啶（A-7）。4-甲基哌啶取代的HC-3的叔胺衍生物（A-4）的效力比其相应的季铵衍生物（A-5）低近10倍。HC-3竞争性抑制胆碱摄取，而A-5非竞争性抑制。通过洗涤，A-5对胆碱摄取的抑制作用很容易逆转。A-5不抑制多巴胺和γ-氨基丁酸的摄取。这些发现表明，HC-3的N-甲基、4-甲基哌啶类似物（A-5）是所有已知的钠依赖性高亲和力胆碱摄取抑制剂中效力最强的，并且该化合物对胆碱摄取的抑制作用是通过一种不同于简单竞争机制的机制介导的。
