Preclinical characterization of selective phosphodiesterase 10A inhibitors: A new therapeutic approach to the treatment of schizophrenia
Preclinical characterization of selective phosphodiesterase 10A inhibitors: A new therapeutic approach to the treatment of schizophrenia
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DOI：
10.1124/jpet.107.132910
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Menniti, F. S.
中科院分区：
文献类型：
--
作者：
Schmidt, C. J.;Chapin, D. S.;Menniti, F. S.
我们最近提出了抑制环核苷酸磷酸二酯酶（PDE）10 A可能代表治疗精神分裂症的新药理学方法的假设（Curr Opin Invest Drug 8：54-59，2007）。PDE 10A在哺乳动物纹状体的中型多棘神经元中高度表达（Brain Res 985：113-126，2003; J Histochem Cytochem 54：1205-1213，2006; Neuroscience 139：597-607，2006），其中假设该酶调节cAMP和cGMP信号级联以影响皮质纹状体丘脑回路中的早期信号处理（Neuropharmacology 51：374-385，2006; Neuropharmacology 51：386-396，2006）。我们目前对PDE 10A的生理作用和PDE 10A抑制剂的治疗效用的理解部分来自罂粟碱的研究，罂粟碱是迄今为止广泛描述的该靶点的唯一药理学工具。然而，该药剂在这方面具有显著的局限性，即，相对较差的效力和选择性以及全身给药后的暴露半衰期非常短。在本报告中，我们描述了一类新的PDE 10A抑制剂的发现，例如TP-10（2-{4-[-吡啶-4-基-1-（2，2，2-三氟-乙基）-1H-吡唑-3-基]-苯氧基甲基}-喹啉琥珀酸），一种具有极大改善的效力、选择性和药物性质的试剂。这些新的药理学工具使研究提供了进一步的证据，即抑制PDE 10A是治疗精神分裂症和基底神经节功能相关疾病的重要新靶点。
We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H- pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.