Meyer E M, Kuryatov A, Gerzanich V, Lindstrom J, Papke R L
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA.
J Pharmacol Exp Ther. 1998 Dec;287(3):918-25.
3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) is a selective partial agonist for rat alpha-7 nicotine receptors with reportedly much lower efficacy for human alpha-7 receptors. Because this drug improves memory-related performance in nonhuman primates, and is presently in a clinical trial for Alzheimer's disease, we investigated the potential effects of its primary human metabolite, 3-(4-hydroxy, 2-methoxy-benzylidene)anabaseine) on human as well as rat nicotinic acetylcholine receptor. 4OH-GTS-21 exhibited a similar level of efficacy for both rat and human alpha-7 receptors expressed in Xenopus oocytes. It displaced high affinity [125I]alpha-bungarotoxin binding to human SK-N-SH cell-membranes (Ki 0.17 microM) and rat PC12 cell-membranes (Ki 0.45 microM). GTS-21 also displaced [125I]alpha-bungarotoxin binding to PC12 cell membranes with high potency (Ki 0.31 microM), but was much less potent in this regard in SK-N-SH cells (23 microM). 4OH-GTS-21 produced less residual inhibition of either the human or rat AChR subtypes than GTS-21 did. To compare the neuroprotective efficacies of GTS-21 and 4OH-GTS-21 in both species, an amyloid-toxicity model (Abeta 25-35) was used. 4OH-GTS-21 was protective in both human and rat cell lines, although GTS-21 was effective only in the latter. These studies suggest that the efficacy of GTS-21 in primates may depend on a pro-drug function.
3-(2,4-二甲氧基亚苄基)去甲斑蝥碱(GTS-21)是大鼠α-7尼古丁受体的选择性部分激动剂，据报道对人类α-7受体的效力要低得多。由于这种药物能改善非人类灵长类动物与记忆相关的表现，且目前正处于针对阿尔茨海默病的临床试验中，我们研究了其主要人体代谢产物3-(4-羟基，2-甲氧基-亚苄基)去甲斑蝥碱)对人类以及大鼠烟碱型乙酰胆碱受体的潜在影响。4OH-GTS-21对非洲爪蟾卵母细胞中表达的大鼠和人类α-7受体表现出相似的效力水平。它能取代高亲和力的[125I]α-银环蛇毒素与人类SK-N-SH细胞膜(Ki 0.17微摩尔)和大鼠PC12细胞膜(Ki 0.45微摩尔)的结合。GTS-21也能高效地取代[125I]α-银环蛇毒素与PC12细胞膜的结合(Ki 0.31微摩尔)，但在这方面对SK-N-SH细胞的效力要低得多(23微摩尔)。4OH-GTS-21对人类或大鼠AChR亚型产生的残余抑制作用均比GTS-21小。为了比较GTS-21和4OH-GTS-21在这两个物种中的神经保护效力，使用了淀粉样毒性模型(Abeta 25-35)。4OH-GTS-21在人类和大鼠细胞系中均具有保护作用，尽管GTS-21仅在后者中有效。这些研究表明，GTS-21在灵长类动物中的效力可能取决于前体药物功能。
