The M1 Muscarinic Positive Allosteric Modulator PQCA Improves Performance on Translatable Tests of Memory and Attention in Rhesus Monkeys
The M1 Muscarinic Positive Allosteric Modulator PQCA Improves Performance on Translatable Tests of Memory and Attention in Rhesus Monkeys
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DOI：
10.1124/jpet.115.226712
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发表时间：
2015-12-01
影响因子：
3.5
通讯作者：
Uslaner, Jason M.
中科院分区：
文献类型：
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作者：
Lange, Henry S.;Cannon, Christopher E.;Uslaner, Jason M.
改善阿尔茨海默病（AD）的治疗是一项重大的未满足的医疗需求，鉴于患者数量的增加和巨大的经济负担，这一需求正变得更加关键。目前的治疗标准是乙酰胆碱酯酶抑制剂（AChEIs），由于其对毒蕈碱和烟碱受体的非选择性激活而受到胃肠道副作用的阻碍。最近，高选择性M1阳性变构调节剂PQCA（1-（4-氰-4-（吡啶-2-基）胡椒苷-1-基）甲基-4-氧-4- h -喹啉-3-羧酸）在多种啮齿动物和非人灵长类动物认知模型中被证明可以改善认知，而不会产生明显的胃肠道副作用。在这里，我们描述了PQCA和AChEI多奈哌齐对非人灵长类动物的两个临床相关且高度可翻译的触摸屏认知任务的影响：配对联想学习（PAL）和持续表现任务（CPT）。东莨菪碱阻断毒蕈碱信号通路对PAL和CPT均产生显著损伤。PQCA和多奈哌齐减轻了东莨菪碱在这两项任务中的缺陷，这两种化合物的作用在程度上相似。此外，亚有效剂量的PQCA和多奈哌齐联合使用可提高PAL性能。这些结果进一步表明，m1阳性变构调节剂，无论是作为单一疗法还是作为当前护理标准的附加疗法，都有可能减少与AD相关的认知缺陷。
Improved treatment of Alzheimer disease (AD) is a significant unmet medical need that is becoming even more critical given the rise in the number of patients and the substantial economic burden. The current standards of care, acetylcholinesterase inhibitors (AChEIs), are hindered by gastrointestinal side effects owing to their nonselective activation of muscarinic and nicotinic receptors. Recently, the highly selective M1 positive allosteric modulator PQCA (1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl) methyl-4-oxo-4 H-quinolizine-3-carboxylic acid) has been demonstrated to improve cognition in a variety of rodent and nonhuman primate cognition models without producing significant gastrointestinal side effects. Here we describe the effect of PQCA and the AChEI donepezil on two clinically relevant and highly translatable touchscreen cognition tasks in nonhuman primates: paired-associates learning (PAL) and the continuous-performance task (CPT). Blockade of muscarinic signaling by scopolamine produced significant impairments in both PAL and CPT. PQCA and donepezil attenuated the scopolamine deficits in both tasks, and the action of these two compounds was similar in magnitude. In addition, the combination of subeffective doses of PQCA and donepezil enhanced PAL performance. These results further suggest that M1-positive allosteric modulators, either as monotherapy or as an add-on to current standards of care, have potential to reduce the cognitive deficits associated with AD.