Vialko Alina, Chałupnik Paulina, Szymańska Ewa
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College in Kraków, PL 30-688 Kraków, Poland.
Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, PL 31-530 Krakow, Poland.
Int J Mol Sci. 2025 Jul 4;26(13):6450. doi: 10.3390/ijms26136450.
Ionotropic glutamate receptors-including -methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors-play a pivotal role in excitatory signaling in the central nervous system (CNS), which is particularly important for learning and memory processes. Among them, AMPA and kainate receptors (known as 'non-NMDA' receptors) have gained increasing attention as therapeutic targets for various CNS disorders. Positive allosteric modulators (PAMs) of these receptors enhance their activity without directly activating them, offering a promising strategy to fine-tune glutamatergic signaling with potentially fewer side effects compared to orthosteric agonists. This review presents a comprehensive overview of recent advances in the development of AMPA and kainate receptor PAMs. We classify the most relevant modulators into main chemotype groups and discuss their binding modes, structure-activity relationships, and efficacy as determined through in vitro and in vivo studies. Additionally, we provide an overview of AMPA receptor PAMs that have entered into clinical trials over the past few decades. The increasing interest in kainate receptor PAMs is also mentioned, underlining their emerging role in future neuropharmacological strategies.
离子型谷氨酸受体，包括N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和海人藻酸受体，在中枢神经系统（CNS）的兴奋性信号传导中起关键作用，这对学习和记忆过程尤为重要。其中，AMPA和海人藻酸受体（被称为“非NMDA”受体）作为各种中枢神经系统疾病的治疗靶点受到越来越多的关注。这些受体的正变构调节剂（PAMs）可增强其活性而不直接激活它们，与正构激动剂相比，这提供了一种有望微调谷氨酸能信号传导且副作用可能更少的策略。本综述全面概述了AMPA和海人藻酸受体PAMs开发的最新进展。我们将最相关的调节剂分类为主要化学类型组，并讨论它们的结合模式、构效关系以及通过体外和体内研究确定的功效。此外，我们概述了在过去几十年中已进入临床试验的AMPA受体PAMs。还提到了对海人藻酸受体PAMs日益增长的兴趣，强调了它们在未来神经药理学策略中正在出现的作用。
