Preclinical Drug Development Grünenthal GmbH Aachen Germany.
Temple University School of Pharmacy Philadelphia Pennsylvania.
Pharmacol Res Perspect. 2018 Nov 28;6(6):e00444. doi: 10.1002/prp2.444. eCollection 2018 Dec.
Cebranopadol (trans-6'-fluoro-4',9'-dihydro--dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ opioid peptide (NOP) and classical opioid receptor (MOP, DOP, and KOP) agonist with highly efficacious and potent activity in a broad range of rodent models of nociceptive, inflammatory, and neuropathic pain as well as limited opioid-type side effects such as respiratory depression. This study was designed to explore contribution and interaction of NOP and classical opioid receptor agonist components to cebranopadol analgesia in the rat spinal nerve ligation (SNL) model. Assessing antihypersensitive activity in SNL rats intraperitoneal (IP) administration of cebranopadol resulted in ED values of 3.3 and 3.58 μg/kg in two independent experiments. Pretreatment (IP) with J-113397 (4.64 mg/kg) a selective antagonist for the NOP receptor or naloxone (1 mg/kg), naltrindole (10 mg/kg), or nor-BNI (10 mg/kg), selective antagonists for MOP, DOP, and KOP receptors, yielded ED values of 14.1, 16.9, 17.3, and 15 μg/kg, respectively. This 4-5 fold rightward shift of the dose-response curves suggested agonistic contribution of all four receptors to the analgesic activity of cebranopadol. Combined pretreatment with a mixture of the antagonists for the three classical opioid receptors resulted in an 18-fold potency shift with an ED of 65.5 μg/kg. The concept of dose equivalence was used to calculate the expected additive effects of the parent compound for NOP and opioid receptor contribution and to compare them with the observed effects, respectively. This analysis revealed a statistically significant difference between the expected additive and the observed effects suggesting intrinsic synergistic analgesic interaction of the NOP and the classical opioid receptor components of cebranopadol. Together with the observation of limited respiratory depression in rats and humans the synergistic interaction of NOP and classical opioid receptor components in analgesia described in the current study may contribute to the favorable therapeutic index of cebranopadol observed in clinical trials.
塞布瑞诺肽（反式-6'-氟-4',9'-二氢--二甲基-4-苯基-螺[环己烷-1,1'-(3'H)-吡喃[3,4-b]吲哚]-4-胺）是一种新型的镇痛孤啡肽/阿片样物质 FQ 肽（NOP）和经典阿片受体（MOP、DOP 和 KOP）激动剂，在广泛的伤害性、炎症性和神经性疼痛的啮齿动物模型中具有高效和强效的活性，并且具有有限的阿片样副作用，如呼吸抑制。本研究旨在探讨 NOP 和经典阿片受体激动剂成分对塞布瑞诺肽在大鼠脊神经结扎（SNL）模型中的镇痛作用的贡献和相互作用。在 SNL 大鼠中评估抗敏活性，腹腔（IP）给予塞布瑞诺肽的 ED 值在两项独立实验中分别为 3.3 和 3.58μg/kg。预先给予（IP）选择性 NOP 受体拮抗剂 J-113397（4.64mg/kg）或纳洛酮（1mg/kg）、纳曲酮（10mg/kg）或 nor-BNI（10mg/kg），MOP、DOP 和 KOP 受体的选择性拮抗剂，得到的 ED 值分别为 14.1、16.9、17.3 和 15μg/kg。这些剂量反应曲线向右移动 4-5 倍表明所有四个受体都对塞布瑞诺肽的镇痛活性有激动作用。联合预先给予三种经典阿片受体拮抗剂混合物导致效力增加 18 倍，ED 值为 65.5μg/kg。使用剂量等效性概念来计算母体化合物对 NOP 和阿片受体贡献的预期相加作用，并将其与观察到的作用进行比较。该分析表明，预期相加作用与观察到的作用之间存在统计学差异，表明塞布瑞诺肽的 NOP 和经典阿片受体成分之间存在内在协同镇痛相互作用。结合在大鼠和人类中观察到的呼吸抑制有限，当前研究中描述的 NOP 和经典阿片受体成分在镇痛中的协同相互作用可能有助于在临床试验中观察到塞布瑞诺肽的有利治疗指数。
