Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin Milwaukee, Milwaukee, WI 53201, USA.
Campbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, Canada.
Molecules. 2023 Jun 14;28(12):4771. doi: 10.3390/molecules28124771.
GABA mediates inhibitory actions through various GABA receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of α2/3 GABAARs can treat mood and anxiety, while α5 GABAA-Rs can treat anxiety, depression, and cognitive performance. GL-II-73 and MP-III-022, α5-positive allosteric modulators have shown promising results in animal models of chronic stress, aging, and cognitive disorders, including MDD, schizophrenia, autism, and Alzheimer's disease. Described in this article is how small changes in the structure of imidazodiazepine substituents can greatly impact the subtype selectivity of benzodiazepine GABAAR. To investigate alternate and potentially more effective therapeutic compounds, modifications were made to the structure of imidazodiazepine to synthesize different amide analogs. The novel ligands were screened at the NIMH PDSP against a panel of 47 receptors, ion channels, including hERG, and transporters to identify on- and off-target interactions. Any ligands with significant inhibition in primary binding were subjected to secondary binding assays to determine their K values. The newly synthesized imidazodiazepines were found to have variable affinities for the benzodiazepine site and negligible or no binding to any off-target profile receptors that could cause other physiological problems.
GABA 通过各种 GABA 受体亚型发挥抑制作用，人类 GABAAR 包含 19 个亚基。GABA 能神经传递的失调与几种精神疾病有关，包括抑郁症、焦虑症和精神分裂症。选择性靶向 α2/3 GABAAR 可治疗情绪和焦虑，而 α5 GABAA-R 可治疗焦虑、抑郁和认知表现。GL-II-73 和 MP-III-022 是 α5 阳性变构调节剂，在慢性应激、衰老和认知障碍的动物模型中显示出有希望的结果，包括 MDD、精神分裂症、自闭症和阿尔茨海默病。本文描述了咪唑并二氮䓬取代基结构的微小变化如何极大地影响苯二氮䓬 GABAAR 的亚型选择性。为了研究替代的、潜在更有效的治疗化合物，对咪唑并二氮䓬的结构进行了修饰，以合成不同的酰胺类似物。将新的配体在 NIMH PDSP 上针对 47 个受体、离子通道（包括 hERG）和转运体进行筛选，以鉴定靶内和靶外相互作用。任何在主要结合中具有显著抑制作用的配体都将进行二次结合测定，以确定其 K 值。新合成的咪唑并二氮䓬对苯二氮䓬结合位点具有不同的亲和力，对任何可能导致其他生理问题的靶外受体几乎没有或没有结合。
