Jarvis Michael F, Yu Haixia, McGaraughty Steve, Wismer Carol T, Mikusa Joe, Zhu Chang, Chu Katharine, Kohlhaas Kathy, Cowart Marlon, Lee Chih Hung, Stewart Andrew O, Cox Bryan F, Polakowski James, Kowaluk Elizabeth A
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA.
Pain. 2002 Mar;96(1-2):107-18. doi: 10.1016/s0304-3959(01)00435-3.
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. N7-((1'R,2'S,3'R,4'S)-2',3'-dihydroxy-4'-amino-cyclopentyl)-4-amino-5-bromo-pyrrolo[2,3-a]pyrimidine (A-286501) is a novel and potent (IC50=0.47 nM) carbocyclic nucleoside AK inhibitor that has no significant activity (IC50 >100 microM) at other sites of ADO interaction (A1, A2A, A3 receptors, ADO transporter, and ADO deaminase) or other (IC50 value >10 microM) neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter reuptake sites and enzymes, including cyclooxygenases-1 and -2. A-286501 showed equivalent potency to inhibit AK from several mammalian species and kinetic studies revealed that A-286501 was a reversible and competitive inhibitor with respect to ADO and non-competitive with respect to MgATP2-. A-286501 was orally effective to reduce nociception in animal models of acute (thermal), inflammatory (formalin and carrageenan), and neuropathic (L5/L6 nerve ligation and streptozotocin-induced diabetic) pain. A-286501 was particularly potent (ED50=1 micromol/kg, p.o.) to reduce carrageenan-induced inflammatory thermal hyperalgesia as compared to its analgesic actions in other pain models (acute and neuropathic) and its ability to alter hemodynamic function and motor performance. A-286501 was also effective to reduce carrageenan-induced paw edema and myeloperoxidase activity, a measure of neutrophil influx (ED50=10 micromol/kg, p.o.), in the injured paw. The anti-nociceptive effects of A-286501 in the L5/L6 nerve injury model of neuropathic pain (ED50=20 micromol/kg, p.o.) were not blocked by the opioid antagonist naloxone, but were blocked by the ADO receptor antagonist, theophylline. Following repeated administration, A-286501 showed less potential to produce tolerance as compared to morphine. Thus, A-286501 is a structurally novel AK inhibitor that effectively attenuates nociception by a non-opioid, non-non-steroidal anti-inflammatory drug ADO, receptor mediated mechanism.
腺苷（ADO）是一种抑制性神经调质，可在有害刺激下提高痛觉阈值。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，AK抑制剂作为镇痛和抗炎药物可能具有治疗潜力。N7-((1'R,2'S,3'R,4'S)-2',3'-二羟基-4'-氨基环戊基)-4-氨基-5-溴吡咯并[2,3-a]嘧啶（A-286501）是一种新型强效（IC50 = 0.47 nM）的碳环核苷AK抑制剂，在ADO相互作用的其他位点（A1、A2A、A3受体、ADO转运体和ADO脱氨酶）或其他（IC50值>10 microM）神经递质和肽受体、离子通道蛋白、神经递质再摄取位点及酶（包括环氧化酶-1和-2）处无显著活性。A-286501对几种哺乳动物来源的AK具有同等抑制效力，动力学研究表明，A-286501对ADO是可逆性竞争性抑制剂，对MgATP2-是非竞争性抑制剂。在急性（热）、炎症（福尔马林和角叉菜胶）和神经性（L5/L6神经结扎和链脲佐菌素诱导的糖尿病性）疼痛动物模型中，A-286501口服有效减轻痛觉。与在其他疼痛模型（急性和神经性）中的镇痛作用及其改变血流动力学功能和运动表现的能力相比，A-286501在减轻角叉菜胶诱导的炎症性热痛觉过敏方面尤为有效（ED50 = 1微摩尔/千克，口服）。A-286501在减轻角叉菜胶诱导的爪部水肿和髓过氧化物酶活性（中性粒细胞浸润的指标，ED50 = 10微摩尔/千克，口服）方面也有效。在神经性疼痛的L5/L6神经损伤模型中，A-286501的抗痛觉作用（ED50 = 20微摩尔/千克，口服）未被阿片类拮抗剂纳洛酮阻断，但被ADO受体拮抗剂茶碱阻断。重复给药后，与吗啡相比，A-286501产生耐受性的可能性较小。因此，A-286501是一种结构新颖的AK抑制剂，通过非阿片类、非甾体抗炎药物ADO受体介导的机制有效减轻痛觉。
