Indications Discovery Research Unit, Pfizer Inc St. Louis, MO, USA.
Front Neurosci. 2011 Sep 9;5:103. doi: 10.3389/fnins.2011.00103. eCollection 2011.
The lack of predictive in vitro models for behavioral phenotypes impedes rapid advancement in neuropharmacology and psychopharmacology. In vivo behavioral assays are more predictive of activity in human disorders, but such assays are often highly resource-intensive. Here we describe the successful application of a computer vision-enabled system to identify potential neuropharmacological activity of two new mechanisms. The analytical system was trained using multiple drugs that are used clinically to treat depression, schizophrenia, anxiety, and other psychiatric or behavioral disorders. During blinded testing the PDE10 inhibitor TP-10 produced a signature of activity suggesting potential antipsychotic activity. This finding is consistent with TP-10's activity in multiple rodent models that is similar to that of clinically used antipsychotic drugs. The CK1ε inhibitor PF-670462 produced a signature consistent with anxiolytic activity and, at the highest dose tested, behavioral effects similar to that of opiate analgesics. Neither TP-10 nor PF-670462 was included in the training set. Thus, computer vision-based behavioral analysis can facilitate drug discovery by identifying neuropharmacological effects of compounds acting through new mechanisms.
缺乏用于行为表型的预测性体外模型，阻碍了神经药理学和精神药理学的快速发展。体内行为测定法对人类疾病中的活性具有更高的预测性，但此类测定法通常需要大量资源。本文中，我们描述了一种成功应用计算机视觉系统来鉴定两种新机制的潜在神经药理活性的方法。分析系统使用了多种临床上用于治疗抑郁症、精神分裂症、焦虑症和其他精神或行为障碍的药物进行训练。在盲测中，PDE10 抑制剂 TP-10 产生了一种具有潜在抗精神病活性的作用特征。这一发现与 TP-10 在多种类似临床应用的抗精神病药物的啮齿动物模型中的活性一致。CK1ε 抑制剂 PF-670462 产生了一种与抗焦虑活性一致的作用特征，且在测试的最高剂量下，其行为效应与阿片类镇痛药相似。TP-10 和 PF-670462 均未包含在训练集中。因此，基于计算机视觉的行为分析可以通过鉴定通过新机制发挥作用的化合物的神经药理作用来促进药物发现。
