Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), 16132 Genova, Italy.
Atomwise Inc., San Francisco, CA 94103, USA.
Int J Mol Sci. 2022 Mar 14;23(6):3127. doi: 10.3390/ijms23063127.
Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.
痕量胺相关受体 5（TAAR5）是一种 G 蛋白偶联受体，属于 TAARs 家族（TAAR1-TAAR9）。TAAR5 表达于嗅上皮，负责感知 3-甲胺（TMA）。然而，最近的研究表明，TAAR5 也表达于边缘脑区，并参与情绪行为和成年神经发生的调节，提示 TAAR5 拮抗可能代表焦虑和抑郁的一种新的治疗策略。我们使用 AtomNet 模型，这是第一个基于结构的药物发现的深度学习神经网络，来识别潜在的 TAAR5 配体，并在体外 BRET 测定中对其进行测试。我们发现了两种具有低至亚微摩尔活性的 mTAAR5 拮抗剂，它们能够抑制 TMA 诱导的 cAMP 产生。此外，这两种化合物还抑制了 mTAAR5 的下游信号，如 CREB 和 ERK 的磷酸化。这两个命中物具有类药性，可用于进一步开发具有潜在抗焦虑和抗抑郁活性的更有效的 TAAR5 配体。
