Adenosine (ADO) is an inhibitory neuromodulator that can increase nociceptive thresholds in response to noxious stimulation. Inhibition of the ADO-metabolizing enzyme adenosine kinase (AK) increases extracellular ADO concentrations at sites of tissue trauma and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. ABT-702 is a novel and potent (IC(50) = 1. 7 nM) non-nucleoside AK inhibitor that has several orders of magnitude selectivity over other sites of ADO interaction (A(1), A(2A), A(3) receptors, ADO transporter, and ADO deaminase). ABT-702 was 1300- to 7700-fold selective for AK compared with a number of other neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter/nucleoside reuptake sites, and enzymes, including cycloxygenases-1 and -2. ABT-702 was equipotent (IC(50) = 1.5 +/- 0. 3 nM) in inhibiting native human AK (placenta), two human recombinant isoforms (AK(long) and AK(short)), and AK from monkey, dog, rat, and mouse brain. Kinetic studies revealed that AK inhibition by ABT-702 was competitive with respect to ADO and noncompetitive with respect to MgATP(2-). AK inhibition by ABT-702 was demonstrated to be reversible after 4 h of dialysis. ABT-702 is orally active and fully efficacious in reducing acute somatic nociception (ED(50) = 8 micromol/kg i.p.; 65 micromol/kg p.o.) in the mouse hot-plate assay. ABT-702 also dose dependently reduced nociception in the phenyl-p-quinone-induced abdominal constriction assay. The antinociceptive effects of ABT-702 in the hot-plate assay were blocked by the nonselective ADO receptor antagonist theophylline, and by the A(1)-selective antagonist cyclopentyltheophylline (10 mg/kg i.p.), but not by a peripherally selective ADO receptor antagonist 8-(p-sulfophenyl)-theophylline (50 mg/kg i.p.), by the A(2A)-selective antagonist 3, 7-dimethyl-1-propargylxanthine (1 mg/kg i.p.) or the opioid antagonist naloxone (5 mg/kg i.p.). Thus, ABT-702 is a novel and potent non-nucleoside AK inhibitor that effectively reduces acute thermal nociception in the mouse by a nonopioid, non-nonsteroidal anti-inflammatory drug, ADO A(1) receptor-mediated mechanism.

中文翻译：

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ABT-702（4-氨基-5-（3-溴苯基）-7-（6-吗啉代吡啶-3-基）吡啶并[2，3-d]嘧啶），一种新型口服有效的腺苷激酶抑制剂，具有镇痛和抗炎症特性：I.小鼠的体外特征和急性镇痛作用。

腺苷（ADO）是一种抑制性神经调节剂，可响应有害刺激而增加伤害性阈值。抑制ADO代谢酶腺苷激酶（AK）会增加组织创伤部位的细胞外ADO浓度，并且AK抑制剂作为止痛药和抗炎药可能具有治疗潜力。ABT-702是一种新型有效的（IC（50）=1。7nM）非核苷AK抑制剂，对ADO相互作用的其他位点具有几个数量级的选择性（A（1），A（2A），A（ 3）受体，ADO转运蛋白和ADO脱氨酶。与许多其他神经递质和肽受体，离子通道蛋白，神经递质/核苷再摄取位点以及酶（包括环加氧酶-1和-2）相比，ABT-702对AK的选择性是1300- 7700倍。ABT-702是等电位的（IC（50）= 1.5 +/- 0。3 nM）抑制天然人类AK（胎盘），两种人类重组同工型（AK（long）和AK（short））和来自猴，狗，大鼠和小鼠脑的AK。动力学研究表明，ABT-702对AK的抑制作用相对于ADO具有竞争性，而对MgATP（2-）则无竞争性。透析4小时后，证明ABT-702对AK的抑制作用是可逆的。在小鼠热板试验中，ABT-702具有口服活性，可有效降低急性体细胞伤害感受（ED（50）= 8 micromol / kg ip； 65 micromol / kg po）。在苯基对醌诱导的腹部收缩试验中，ABT-702还剂量依赖性地降低了伤害感受。非选择性ADO受体拮抗剂茶碱和A（1）选择性拮抗剂环戊基茶碱（10 mg / kg ip）阻断了ABT-702在热板试验中的抗伤害作用，但不是由外周选择性ADO受体拮抗剂8-（p-磺基苯基）-茶碱（50 mg / kg ip），而是由A（2A）选择拮抗剂3，7-二甲基-1-炔丙基黄嘌呤（1 mg / kg ip） ）或阿片拮抗剂纳洛酮（5 mg / kg ip）。因此，ABT-702是一种新型有效的非核苷AK抑制剂，可通过非阿片类，非非甾体抗炎药ADO A（1）受体介导的机制有效降低小鼠的急性热伤害感受。