Smith Sean M, Uslaner Jason M, Yao Lihang, Mullins Chadwick M, Surles Nathan O, Huszar Sarah L, McNaughton Caitlyn H, Pascarella Danette M, Kandebo Monika, Hinchliffe Richard M, Sparey Tim, Brandon Nicholas J, Jones Brian, Venkatraman Shankar, Young Mary Beth, Sachs Nancy, Jacobson Marlene A, Hutson Peter H
Department of Schizophrenia Research, Merck and Co., Inc., WP46-100, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486, USA.
J Pharmacol Exp Ther. 2009 Mar;328(3):921-30. doi: 10.1124/jpet.108.147884. Epub 2008 Dec 16.
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 (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 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.
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一些缺陷的基础。改善NMDA受体功能的一种方法是通过增加内源性协同激动剂D-丝氨酸的可利用性来提高NMDA受体上甘氨酸调节位点的占有率。在此，我们对一种新型D-氨基酸氧化酶（DAAO）抑制剂化合物8 [4H-噻吩并[3,2-b]吡咯-5-羧酸]进行了特性分析，并将其与D-丝氨酸进行了比较。化合物8在体外是一种对人（IC50，145 nM）和大鼠（IC50，114 nM）DAAO具有中等效力的抑制剂。在大鼠中，化合物8（200 mg/kg）使肾脏DAAO活性降低约96%，使脑DAAO活性降低约80%。DAAO活性的这种显著降低导致血浆（为对照组的220%）和脑脊液（CSF；为对照组的175%）中D-丝氨酸浓度显著升高（p < 0.001）。然而，化合物8未能显著影响苯丙胺诱导的精神运动活性、伏隔核多巴胺释放或MK-801（马来酸氯氮平）诱导的大鼠新物体识别缺陷。相比之下，高剂量的D-丝氨酸可减弱苯丙胺诱导的精神运动活性和多巴胺释放，还可改善新物体识别的表现。行为有效剂量的D-丝氨酸（1280 mg/kg）使CSF中D-丝氨酸水平比化合物8最大剂量所达到的水平高出40倍。这些发现表明，对DAAO的药理学抑制可显著提高外周和中枢神经系统中D-丝氨酸的浓度。然而，急性抑制DAAO似乎不足以将D-丝氨酸增加到产生与高剂量外源性D-丝氨酸给药后观察到的抗精神病和认知增强作用所需的浓度。
