DL-AP5 is an racemic form of a selective NMDA (N-methyl-D-aspartate) receptor antagonist. D-AP5 is the active (-) stereoisomer, which can competitively inhibit the glutamate binding site of the NMDA receptor (Kd = 1.4μM), while the (+) isomer (L-AP5) shows relatively low NMDA receptor antagonist activity [1]. NMDA is a glutamate-gated ion channel widely present in the central nervous system and plays a crucial role in excitatory synaptic transmission [2]. DL-AP5 has significant analgesic activity and can block the channels in rabbit retina [3-4].
In vitro, DL-AP5 (100μM; 6h) can inhibit the level of Arc/Arg3.1 protein in cortical neurons induced by glutamate [5]. Pre-incubation with DL-AP5 (100μM; 20min) reduces the phosphorylation level of intermediate filament (IF) protein in rat brain cortex slices treated with α-ketoisocaproic acid (KIC) [6].
In vivo, DL-AP5 (20, 40mM; 14 days; intracerebroventricular injection) significantly reduces the vaginal opening age of immature female rats and inhibits the effect of intravenous injection of NMDA on the response to luteinizing hormone [7]. DL-AP5 (0, 2.5, 5 and 10nM; 10μl, single-dose intracerebroventricular injection) increases the food intake of broiler chickens in the 3-hour food deprivation (FD3) model in a dose-dependent manner and weakens the reduction in food consumption caused by the injection of ghrelin [8].
References:
[1] Evans, R.H., Francis, A.A., Jones, A.W., et al. The effects of a series of ω-phosphonic α-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations. Br. J. Pharmacol. 75(1), 65-75 (1982).
[2] Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol. 2007;7(1):39-47.
[3] Jafari-Sabet M. NMDA receptor blockers prevents the facilitatory effects of post-training intra-dorsal hippocampal NMDA and physostigmine on memory retention of passive avoidance learning in rats. Behav Brain Res. 2006;169(1):120-127.
[4] Massey SC, Miller RF. N-methyl-D-aspartate receptors of ganglion cells in rabbit retina. J Neurophysiol. 1990;63(1):16-30.
[5] Chen T, Zhu J, Yang LK, Feng Y, Lin W, Wang YH. Glutamate-induced rapid induction of Arc/Arg3.1 requires NMDA receptor-mediated phosphorylation of ERK and CREB. Neurosci Lett. 2017;661:23-28.
[6] Funchal C, Zamoner A, dos Santos AQ, Loureiro SO, Wajner M, Pessoa-Pureur R. Alpha-ketoisocaproic acid increases phosphorylation of intermediate filament proteins from rat cerebral cortex by mechanisms involving Ca2+ and cAMP. Neurochem Res. 2005;30(9):1139-1146.
[7] Wu F C W, Howe D C, Naylor A M. N‐Methyl‐DL‐Aspartate Receptor Antagonism by D‐2‐Amino‐5‐Phosphonovaleric Acid Delays Onset of Puberty in the Female Rat[J]. Journal of Neuroendocrinology, 1990, 2(5): 627-631.
[8] Taati M, Nayebzadeh H, Zendehdel M. The effects of DL-AP5 and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived broiler cockerels. J Physiol Biochem. 2011;67(2):217-223.
DL-AP5是一种选择性NMDA（N-methyl-D-aspartate）受体拮抗剂的外消旋体。D-AP5是活性的（-）立体异构体，能竞争性地抑制NMDA受体的谷氨酸结合位点（Kd=1.4μM），而（+）异构体（L-AP5）则显示出相当低的NMDA受体拮抗剂活性 [1]。NMDA是广泛存在于中枢神经系统中的谷氨酸门控离子通道，在兴奋性突触传递中起着关键作用 [2]。DL-AP5具有明显的镇痛活性，并能阻断兔视网膜的通道 [3-4]。
在体外，DL-AP5（100μM; 6h）能够抑制谷氨酸诱导的皮质神经元中Arc/Arg3.1蛋白的水平 [5]。DL-AP5预孵育（100μM; 20min）降低了α-ketoisocaproic acid（KIC）处理的大鼠脑皮质切片中intermediate filament（IF）蛋白的磷酸化水平 [6]。
在体内，DL-AP5（20, 40mM; 14 days; 脑室内注射）显著减小了未成熟雌性大鼠的阴道开口年龄，并且抑制了静脉注射NMDA对黄体生成素反应的影响 [7]。DL-AP5（0, 2.5, 5和10nM; 10μl, 单剂量脑室内注射）以剂量依赖性的方式增加了3小时食物缺乏(FD3)模型肉鸡的食物摄入量，并减弱了注射生长素（ghrelin）引起的食物消耗减少 [8]。