Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Anesthesiology and Intensive Care Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.
Department of Drug Discovery and In Vitro Pharmacology, Laboratorios Dr. Esteve, Parc Científic de Barcelona, Barcelona, Spain.
Sci Rep. 2018 Jun 12;8(1):8965. doi: 10.1038/s41598-018-27313-4.
Novel pain killers without adverse effects are urgently needed. Opioids induce central and intestinal side effects such as respiratory depression, sedation, addiction, and constipation. We have recently shown that a newly designed agonist with a reduced acid dissociation constant (pK) abolished pain by selectively activating peripheral μ-opioid receptors (MOR) in inflamed (acidic) tissues without eliciting side effects. Here, we extended this concept in that pK reduction to 7.22 was achieved by placing a fluorine atom at the ethylidene bridge in the parental molecule fentanyl. The new compound (FF3) showed pH-sensitive MOR affinity, [S]-GTPγS binding, and G protein dissociation by fluorescence resonance energy transfer. It produced injury-restricted analgesia in rat models of inflammatory, postoperative, abdominal, and neuropathic pain. At high dosages, FF3 induced sedation, motor disturbance, reward, constipation, and respiratory depression. These results support our hypothesis that a ligand's pK should be close to the pH of injured tissue to obtain analgesia without side effects.
急需新型无不良反应的止痛药物。阿片类药物会引起中枢和肠道副作用,如呼吸抑制、镇静、成瘾和便秘。我们最近表明,一种新设计的具有较低酸离解常数(pK)的激动剂通过选择性激活炎症(酸性)组织中的外周μ-阿片受体(MOR)来消除疼痛,而不会引起副作用。在这里,我们将这一概念扩展到通过在母体分子芬太尼的亚乙基桥上放置一个氟原子将 pK 降低到 7.22。新化合物(FF3)表现出 pH 敏感的 MOR 亲和力、[S]-GTPγS 结合和通过荧光共振能量转移的 G 蛋白解离。它在炎症、术后、腹部和神经性疼痛的大鼠模型中产生了限制在损伤部位的镇痛作用。在高剂量下,FF3 会引起镇静、运动障碍、奖励、便秘和呼吸抑制。这些结果支持我们的假设,即配体的 pK 应该接近损伤组织的 pH 值,以获得无副作用的镇痛效果。