The Behavioral and Neurochemical Effects of a Novel D-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and D-Serine
The Behavioral and Neurochemical Effects of a Novel D-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and D-Serine
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DOI：
10.1124/jpet.108.147884
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Hutson, Peter H.
中科院分区：
文献类型：
--
作者：
Smith, Sean M.;Uslaner, Jason M.;Hutson, Peter H.
多项研究表明，N-甲基-D-天冬氨酸（NMDA）受体功能减退是精神分裂症相关缺陷的基础。改善NMDA受体功能的一种方法是通过增加内源性凝血剂D-丝氨酸的可用性来提高NMDA受体上甘氨酸调节位点的占有率。本文报道了一种新的D-氨基酸氧化酶（DAAO）抑制剂化合物8 [4 H-噻吩并[3，2-B]吡咯-5-羧酸]的结构和性质，并与D-丝氨酸进行了比较。化合物8是体外人（IC 50，145 nM）和大鼠（IC 50，114 nM）DAAO的中等有效抑制剂。在大鼠中，化合物8（200 mg/kg）使肾DAAO活性降低了类似于96%，并且使脑DAAO活性降低了类似于80%。DAAO活性的这种显著降低导致血浆（对照的220%）和脑脊液（CSF;对照的175%）D-丝氨酸浓度的显著（p < 0.001）升高。然而，化合物8未能显着影响安非他明诱导的精神活动，核多巴胺释放，或MK-801（马来酸地佐环平）诱导的缺陷，在新的物体识别大鼠。相比之下，高剂量的D-丝氨酸减弱了安非他明诱导的精神活动和多巴胺释放，并提高了新物体识别的性能。行为有效剂量的D-丝氨酸（1280 mg/kg）使D-丝氨酸的CSF水平增加到最大剂量的化合物8所达到的水平的40倍以上。这些发现表明，DAAO的药理学抑制显著增加外周和中枢神经系统中的D-丝氨酸浓度。然而，DAAO的急性抑制似乎不足以将D-丝氨酸增加到产生抗精神病药和认知增强作用所需的浓度，所述抗精神病药和认知增强作用类似于施用高剂量外源性D-丝氨酸后观察到的那些。
Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b] pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC50, 145 nM) and rat (IC50, 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by similar to 96% and brain DAAO activity by similar to 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.