Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonists
Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonists
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DOI：
10.1124/jpet.114.213694
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发表时间：
2014-06-01
影响因子：
3.5
通讯作者：
Frosch, Stefanie
中科院分区：
文献类型：
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作者：
Linz, Klaus;Christoph, Thomas;Frosch, Stefanie
Cebranopadol（反式-6 '-氟-4'，9 '-二氢-N，N-二甲基-4-苯基螺[环己烷-1，1'（3 ' H）-吡喃并[3，4-B]吲哚]-4-胺）是一种新型镇痛药痛敏肽/阿片肽FQ肽（NOP）和阿片受体激动剂[K-1（nM）/EC 50（nM）/相对功效（%）：人NOP受体0.9/13.0/89;人μ-阿片肽（MOP）受体0.7/1.2/104;人κ-阿片肽受体2.6/17/67;人δ-阿片肽受体18/110/105]。西博帕多在几种急性和慢性疼痛（甩尾、类风湿性关节炎、骨癌、脊神经结扎、糖尿病性神经病变）的大鼠模型中表现出高度有效的抗伤害感受和抗过敏作用，静脉内给药后的ED 50值为0.5-5.6 μ g/kg，口服给药后为25.1 μ g/kg。与选择性MOP受体激动剂相比，西博帕多在慢性神经性疼痛模型中比在急性伤害性疼痛模型中更有效。西博帕多的作用持续时间长（在大鼠甩尾试验中，静脉注射12 μ g/kg后长达7小时;口服55 μ g/kg后> 9小时）。西博帕多在脊神经结扎模型中的抗过敏活性通过选择性NOP受体拮抗剂J-113397[1-[（3R，4 R）-1-环辛基甲基-3-羟甲基-4-哌啶基]-3-乙基-1，3-二氢-2H-苯并咪唑-2-酮]或阿片受体拮抗剂纳洛酮预处理而部分逆转，表明NOP和阿片受体激动均参与该活性。与等镇痛剂量的吗啡相比，慢性压迫性损伤模型中镇痛耐受性的发展明显延迟（分别在第26天和第11天完全耐受）。与吗啡不同，西博帕多在镇痛剂量范围内和超过镇痛剂量范围时不会破坏运动协调和呼吸。西博帕多通过其对NOP和阿片受体的激动作用的组合，在各种疼痛模型中提供高度强效和有效的镇痛，具有有利的副作用特征。
Cebranopadol (trans-6 '-fluoro-4 ',9 '-dihydro-N, N-dimethyl-4-phenylspiro[cyclohexane-1,1 '(3 ' H)- pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [K-i (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 mu g/kg after intravenous and 25.1 mu g/kg after oral administration. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol's duration of action is long (up to 7 hours after intravenous 12 mu g/kg;> 9hours after oral 55 mu g/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side effect profile.