Psychiatric Research, Merck Sharp & Dohme Corp., West Point, Pennsylvania, USA.
ACS Chem Neurosci. 2012 Feb 15;3(2):129-40. doi: 10.1021/cn200109w. Epub 2011 Nov 14.
Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.
前额叶皮层中多巴胺神经递质的传递减少被认为是与精神分裂症相关的阴性症状和认知缺陷的原因；因此，选择性增强前额叶皮层中多巴胺神经递质传递的化合物可能具有治疗潜力。抑制儿茶酚-O-甲基转移酶（COMT，EC 2.1.1.6）提供了一个独特的优势，因为这种酶是皮质区域中多巴胺消除的主要机制。由于膜结合 COMT（MB-COMT）是人类大脑中的主要同工酶，因此完成了高通量筛选（HTS）以鉴定新型 MB-COMT 特异性抑制剂。随后的优化导致了新型非硝基儿茶酚 COMT 抑制剂的鉴定，其中一些与 MB-COMT 特异性相互作用。对化合物进行了体外对人和大鼠 MB 以及可溶性（S）-COMT 的功效特征分析。选择的化合物被施用于雄性 Wistar 大鼠，并测定了离体 COMT 活性、血浆和脑脊液（CSF）中的化合物水平以及 CSF 多巴胺代谢物水平，作为临床前功效的衡量标准。最后，与托卡朋相比，新型非硝基儿茶酚 COMT 抑制剂显示出较弱的线粒体膜电位（MMP）解偶联作用，以及非肝毒性恩他卡朋，从而降低了肝毒性的风险。
