Tam S W, Zaczek R
Central Nervous System Diseases Research, DuPont Merck Pharmaceutical Company Wilmington, Delaware, USA.
Adv Exp Med Biol. 1995;363:47-56.
Linopirdine (DuP 996, AVIVA), currently in Phase III clinical trial for the treatment of Alzheimer's disease, is a representative of a class of novel molecules which enhances the stimulus-evoked but not basal release of several neurotransmitters including ACh, DA, 5-HT and Glu. Linopiridine has been shown to enhance ACh release in the hippocampus in vivo. In addition, linopiridine produces a number of effects including EEG patterns of enhanced vigilance, induction of c-fos expression in cerebral cortex, reduction of the increase of cerebral glucose utilization induced by hypoxia, and improved performance in animal models of learning and memory. The specific action of linopiridine on depolarized neurons but not on basal release suggests that compounds of this class will enhance normal brain activity and not lead to a non-specific activation. Furthermore, the effect of linopiridine on multiple neurotransmitter systems that are deficient in Alzheimer's disease suggests that this class of agents may be more efficacious in the treatment of dementia than therapies aimed at individual neurotransmitters systems.
利诺吡啶（DuP 996，AVIVA）目前正处于治疗阿尔茨海默病的III期临床试验阶段，它是一类新型分子的代表，这类分子能增强包括乙酰胆碱（ACh）、多巴胺（DA）、5-羟色胺（5-HT）和谷氨酸（Glu）在内的多种神经递质由刺激诱发的释放，但不影响其基础释放。利诺吡啶已被证实在体内能增强海马体中乙酰胆碱的释放。此外，利诺吡啶还产生多种效应，包括提高警觉性的脑电图模式、诱导大脑皮层中c-fos表达、减少缺氧诱导的大脑葡萄糖利用增加，以及改善学习和记忆动物模型中的表现。利诺吡啶对去极化神经元有特异性作用，而对基础释放无作用，这表明这类化合物将增强正常脑活动，而不会导致非特异性激活。此外，利诺吡啶对阿尔茨海默病中缺乏的多种神经递质系统有作用，这表明这类药物在治疗痴呆方面可能比针对单个神经递质系统的疗法更有效。
