Jarvis M F, Yu H, Kohlhaas K, Alexander K, Lee C H, Jiang M, Bhagwat S S, Williams M, Kowaluk E A
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
J Pharmacol Exp Ther. 2000 Dec;295(3):1156-64.
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.
腺苷（ADO）是一种抑制性神经调质，可在对有害刺激作出反应时提高痛觉阈值。抑制ADO代谢酶腺苷激酶（AK）可增加组织创伤部位的细胞外ADO浓度，并且AK抑制剂作为镇痛和抗炎剂可能具有治疗潜力。ABT - 702是一种新型强效（IC50 = 1.7 nM）非核苷类AK抑制剂，与ADO相互作用的其他位点（A1、A2A、A3受体、ADO转运体和ADO脱氨酶）相比具有几个数量级的选择性。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（包括环氧化酶-1和-2）相比，ABT - 702对AK的选择性高1300至7700倍。ABT - 702在抑制天然人AK（胎盘）、两种人重组同工型（AK长型和AK短型）以及来自猴、狗、大鼠和小鼠脑的AK方面具有同等效力（IC50 = 1.5±0.3 nM）。动力学研究表明，ABT - 702对AK的抑制作用相对于ADO是竞争性的，相对于MgATP2-是非竞争性的。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口服有效且能完全有效减轻急性躯体痛觉（腹腔注射ED50 = 8 μmol/kg；口服65 μmol/kg）。在对苯醌诱导的腹部收缩试验中，ABT - 702也呈剂量依赖性地减轻痛觉。在热板试验中，ABT - 702的抗痛觉作用被非选择性ADO受体拮抗剂茶碱以及A1选择性拮抗剂环戊基茶碱（腹腔注射10 mg/kg）阻断，但未被外周选择性ADO受体拮抗剂8 - （对磺基苯基）茶碱（腹腔注射50 mg/kg）、A2A选择性拮抗剂3,7 - 二甲基 - 1 - 炔丙基黄嘌呤（腹腔注射1 mg/kg）或阿片类拮抗剂纳洛酮（腹腔注射5 mg/kg）阻断。因此，ABT - 702是一种新型强效非核苷类AK抑制剂，通过非阿片类、非非甾体抗炎药、ADO A1受体介导的机制有效减轻小鼠的急性热痛觉。
