PMPA (NAALADase inhibitor)

PMPA是一种选择性的N-乙酰基化-α-连接的酸性二肽酶(NAALADase)抑制剂,Ki值为275 pM[1].

NAALADase(也称GCPII)是一种存在于膜中的锌金属酶,参与将神经肽N-乙酰天冬氨酰谷氨酸(NAAG)催化成萘乙酸(NAA)和谷氨酸的过程.研究表明,在神经/前列腺组织及癌症中,NAALADase具有最高表达,且NAALADase的抑制对前列腺癌的神经保护作用\检测\成像及治疗方面产生了各种效应[2] [3].

PMPA是一种强效的NAALADase抑制剂,具有比报道过的NAALADase抑制剂ZJ43更高的活性.在雄性C57/BL小鼠模型中,高剂量的PMPA抑制吗啡耐受的发展(类似于7.5 mg/kg的NMDA受体拮抗剂美金刚的效用),然而其对戒断的严重程度没有效用.浓度为100 mg/kg的PMPA也显著增强吗啡戒断,但是抑制吗啡诱发的条件性位置偏爱的获得与表达,这表明NAALADase参与阿片类药物成瘾现象[4].在训练期间,PMPA增加小鼠进入暗箱的潜伏期,且150 mg/kg剂量的PMPA损害自发交换,减少Y-迷宫任务中的运动,这表明,PMPA通过NAALADase的抑制作用影响小鼠学习记忆任务[5].

参考文献：
[1].  Tiffany, C.W., et al., Binding of the glutamate carboxypeptidase II (NAALADase) inhibitor 2-PMPA to rat brain membranes. Eur J Pharmacol, 2001. 427(2): p. 91-6.
[2].  Barinka, C., et al., Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer. Curr Med Chem, 2012. 19(6): p. 856-70.
[3].  Slusher, B.S., et al., Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat Med, 1999. 5(12): p. 1396-402.
[4].  Popik, P., et al., Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA. Neuropsychopharmacology, 2003. 28(3): p. 457-67.
[5].  Lukawski, K., R.M. Kaminski, and S.J. Czuczwar, Effects of selective inhibition of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) on mice in learning and memory tasks. Eur J Pharmacol, 2008. 579(1-3): p. 202-7.