正变构型 AMPA 受体调节剂在神经精神疾病治疗中的应用：一条漫长而曲折的道路。
Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road.
机构信息
Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
School of Medicine and Surgery, University of Milano-Bicocca, Italy.
出版信息
Drug Discov Today. 2021 Dec;26(12):2816-2838. doi: 10.1016/j.drudis.2021.07.027. Epub 2021 Aug 3.
Abstract
Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed.
摘要
谷氨酸能传递广泛涉及神经精神疾病，而氯胺酮通过调节α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）信号来产生快速抗抑郁作用的发现，激发了人们对该领域的重新关注。本综述探讨了处于不同开发阶段的、直接和间接正向调节 AMPAR 的神经精神疾病治疗药物。尽管有很有前景的临床前研究，但很少有直接和间接的 AMPAR 正变构调节剂能通过早期临床开发。低效力等挑战给有效实施带来了障碍。然而，AMPAR 的功能复杂性使它们有别于其他药物靶点，并允许在药物发现中具有特异性。最终可能会开发出更多通过正向 AMPAR 调节治疗神经精神疾病的有效治疗方法。
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