Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
Curr Med Chem. 2019;26(25):4885-4913. doi: 10.2174/0929867326666190710172002.
Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.
精神分裂症是一种慢性精神疾病，影响着全球约 1/100 的人，导致持续的情感和认知障碍。未经治疗的精神分裂症会导致生活质量恶化和过早死亡。尽管多巴胺 D2 受体拮抗剂对精神分裂症阳性症状的临床疗效支持了该疾病的多巴胺假说，但这些药物对阴性和认知症状的耐药性表明其病理生理学还涉及其他系统。许多研究表明，谷氨酸稳态异常可能与精神分裂症的所有三组症状有关。科学考虑还包括γ-氨基丁酸能和 5-羟色胺能神经递质的传递障碍以及免疫系统的作用。本文旨在更新关于非多巴胺能药物的发现和开发的最新报告，这些药物可能减轻精神分裂症的阳性、阴性和认知症状，并且可能是目前使用的抗精神病药物的替代药物。本文综述了针对代谢型谷氨酸受体、γ-氨基丁酸 A 型受体、α7 烟碱型乙酰胆碱受体、甘氨酸转运体 1 和糖原合酶激酶 3 的代表性化合物的化学结构，以及它们在精神分裂症中的有效性的体外和体内研究结果。还介绍了评估测试化合物安全性和疗效的临床试验结果。最后，关注了具有 5-羟色胺受体亲和力或磷酸二酯酶抑制活性的多功能配体作为寻找精神分裂症患者专用药物的新策略。
