Bontempi Bruno, Whelan Kevin T, Risbrough Victoria B, Lloyd G Kenneth, Menzaghi Frédérique
Merck Research Laboratories, La Jolla, CA, USA.
Neuropsychopharmacology. 2003 Jul;28(7):1235-46. doi: 10.1038/sj.npp.1300150. Epub 2003 Apr 2.
Several studies have demonstrated the importance of nicotinic mechanisms in the pathophysiology of neurodegenerative and cognitive disorders, warranting the search and development of novel nicotinic ligands as potential therapeutic agents. The present study was designed to assess whether the subtype-selective nicotinic acetylcholine receptor (nAChR) ligand SIB-1553A [(+/-)-4-([2-(1-methyl-2-pyrrolidinyl)ethyl]thio)phenol hydrochloride], with predominant agonist activity at beta4 subunit-containing human nAChRs, and no activity at muscle nAChR subtypes, could enhance cognitive performance in rodents with a more desirable safety/tolerability profile as compared to the nonselective prototypic nAChR ligand nicotine. SIB-1553A was equi-efficacious to nicotine in improving working memory performance in scopolamine-treated mice as measured by increased alternation in a T-maze, and was more efficacious than nicotine in improving the baseline cognitive performance of aged mice. This effect on working memory was confirmed in a delayed nonmatching to place task using the eight-arm radial maze. SIB-1553A produced dose-dependent side effects (ie motor deficits and seizures), although these effects were observed at doses 12 to 640-fold above those required to increase cognitive performance. Overall, SIB-1553A was significantly less potent than nicotine in eliciting these undesirable effects. Thus, the subtype-selective profile of SIB-1553A appears to translate into a more efficacious and better tolerated nAChR ligand as compared to nicotine. In the present studies, cognitive enhancement induced by SIB-1553A was similar in magnitude to that produced by the clinically efficacious acetylcholinesterase inhibitor donepezil. Taken together, the present data confirm the importance of nAChR subtypes in modulating cognitive processes, and suggest that activation of nAChR subtypes by selective nAChR ligands may be a viable approach to enhance cognitive performance.
多项研究已证明烟碱机制在神经退行性疾病和认知障碍病理生理学中的重要性，这使得人们有必要寻找和开发新型烟碱配体作为潜在治疗药物。本研究旨在评估亚型选择性烟碱型乙酰胆碱受体（nAChR）配体SIB-1553A [（±）-4-（[2-（1-甲基-2-吡咯烷基）乙基]硫代）苯酚盐酸盐]，其对含β4亚基的人nAChR具有主要激动剂活性，而对肌肉nAChR亚型无活性，与非选择性原型nAChR配体尼古丁相比，是否能在啮齿动物中增强认知能力，同时具有更理想的安全性/耐受性。通过T迷宫中交替次数增加来衡量，SIB-1553A在改善东莨菪碱处理小鼠的工作记忆表现方面与尼古丁等效，并且在改善老年小鼠的基线认知表现方面比尼古丁更有效。这种对工作记忆的影响在使用八臂放射状迷宫的延迟位置不匹配任务中得到证实。SIB-1553A产生剂量依赖性副作用（即运动缺陷和癫痫发作），尽管这些效应在比提高认知表现所需剂量高12至640倍的剂量下才观察到。总体而言，SIB-1553A引发这些不良效应的效力明显低于尼古丁。因此，与尼古丁相比，SIB-1553A的亚型选择性特征似乎转化为一种更有效且耐受性更好的nAChR配体。在本研究中，SIB-1553A诱导的认知增强程度与临床有效的乙酰胆碱酯酶抑制剂多奈哌齐产生的认知增强程度相似。综上所述，目前的数据证实了nAChR亚型在调节认知过程中的重要性，并表明通过选择性nAChR配体激活nAChR亚型可能是增强认知表现的可行方法。
