Mnemosyne Pharmaceuticals, Inc. Providence, RI, USA.
Curr Top Med Chem. 2013;13(1):26-54. doi: 10.2174/1568026611313010005.
Schizophrenia is a highly debilitating mental disorder which afflicts approximately 1% of the global population. Cognitive and negative deficits account for the lifelong disability associated with schizophrenia, whose symptoms are not effectively addressed by current treatments. New medicines are needed to treat these aspects of the disease. Neurodevelopmental, neuropathological, genetic, and behavioral pharmacological data indicate that schizophrenia stems from a dysfunction of glutamate synaptic transmission, particularly in frontal cortical networks. A number of novel pre- and postsynaptic mechanisms affecting glutamatergic synaptic transmission have emerged as viable targets for schizophrenia. While developing orthosteric glutamatergic agents for these targets has proven extremely difficult, targeting allosteric sites of these targets has emerged as a promising alternative. From a medicinal chemistry perspective, allosteric sites provide an opportunity of finding agents with better drug-like properties and greater target specificity. Furthermore, allosteric modulators are better suited to maintaining the highly precise temporal and spatial aspects of glutamatergic synaptic transmission. Herein, we review neuropathological and genomic/genetic evidence underscoring the importance of glutamate synaptic dysfunction in the etiology of schizophrenia and make a case for allosteric targets for therapeutic intervention. We review progress in identifying allosteric modulators of AMPA receptors, NMDA receptors, and metabotropic glutamate receptors, all with the aim of restoring physiological glutamatergic synaptic transmission. Challenges remain given the complexity of schizophrenia and the difficulty in studying cognition in animals and humans. Nonetheless, important compounds have emerged from these efforts and promising preclinical and variable clinical validation has been achieved.
精神分裂症是一种高度致残的精神障碍，影响全球大约 1%的人口。认知和阴性症状导致了与精神分裂症相关的终身残疾，而目前的治疗方法并不能有效解决这些症状。需要新的药物来治疗这种疾病的这些方面。神经发育、神经病理学、遗传学和行为药理学数据表明，精神分裂症源于谷氨酸突触传递的功能障碍，特别是在前额皮质网络中。许多新的突触前和突触后机制影响谷氨酸能突触传递，已成为精神分裂症的可行靶点。虽然开发针对这些靶点的正位谷氨酸能药物已被证明极其困难，但靶向这些靶点的变构位点已成为一种有前途的替代方法。从药物化学的角度来看，变构位点为寻找具有更好药物特性和更高靶标特异性的药物提供了机会。此外，变构调节剂更适合维持谷氨酸能突触传递的高度精确的时间和空间方面。本文综述了神经病理学和基因组/遗传学证据，强调了谷氨酸突触功能障碍在精神分裂症发病机制中的重要性，并提出了变构靶点作为治疗干预的候选。我们回顾了鉴定 AMPA 受体、NMDA 受体和代谢型谷氨酸受体变构调节剂的进展，所有这些都是为了恢复生理谷氨酸能突触传递。鉴于精神分裂症的复杂性以及在动物和人类中研究认知的困难，挑战依然存在。尽管如此，这些努力已经产生了重要的化合物，并在临床前和临床验证方面取得了有希望的进展。
