Codd Ellen E, Carson John R, Colburn Raymond W, Stone Dennis J, Van Besien Christopher R, Zhang Sui-Po, Wade Paul R, Gallantine Elizabeth L, Meert Theo F, Molino Lory, Pullan Shirley, Razler Christine M, Dax Scott L, Flores Christopher M
Research and Early Development, Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA 19477, USA.
J Pharmacol Exp Ther. 2009 Apr;329(1):241-51. doi: 10.1124/jpet.108.146969. Epub 2009 Jan 16.
Mu-opioid analgesics are a mainstay in the treatment of acute and chronic pain of multiple origins, but their side effects, such as constipation, respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the up-regulation and membrane targeting of the delta-opioid receptor (DOR) following inflammation and the consequent enhanced therapeutic effect of delta-opioid agonists have enlivened the search for delta-opioid analgesic agents. JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a naltrindole sensitive DOR potency of 5.6 nM (5'-O-(3-[(35)S]thio)triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test. In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike ibuprofen, JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose, JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike morphine, JNJ-20788560 did not exhibit respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of opioid (mu or delta) antagonists. Coupled with the previously published lack of self-administration behavior of the compound by alfentanil-trained primates, these findings strongly recommend delta-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.
μ-阿片类镇痛药是治疗多种病因引起的急慢性疼痛的主要药物,但它们的副作用,如便秘、呼吸抑制和成瘾性,会对患者产生不利影响。最近的研究表明,炎症后δ-阿片受体(DOR)上调并靶向细胞膜,从而增强了δ-阿片激动剂的治疗效果,这激发了人们对δ-阿片类镇痛药的探索。JNJ-20788560 [9-(8-氮杂双环-[3.2.1]辛-3-亚基)-9H-占吨-3-羧酸二乙酰胺] 对DOR的亲和力为2.0 nM(大鼠脑皮质结合试验),对纳曲吲哚敏感的DOR效价为5.6 nM(5'-O-(3-[(35)S]硫代)三磷酸试验)。该化合物在大鼠酵母聚糖辐射热试验中的口服效价为7.6 mg/kg,在大鼠完全弗氏佐剂辐射热试验中的口服效价为13.5 mg/kg,但在未发炎的辐射热试验中几乎无活性。在有限的研究中,未观察到该化合物的抗痛觉过敏或镇痛作用产生耐受性。与布洛芬不同,JNJ-20788560不会引起胃肠道(GI)糜烂。尽管吗啡在所有测试剂量下均会降低胃肠蠕动,且在最高剂量时几乎达到完全效应,但JNJ-20788560在最低剂量时不会延迟转运,在最高给药剂量时仅降低11%。与吗啡不同,JNJ-20788560未表现出呼吸抑制(血气分析),给予阿片类(μ或δ)拮抗剂也未引发戒断症状。再加上之前发表的关于经阿芬太尼训练的灵长类动物不会自行服用该化合物的研究结果,这些发现强烈推荐使用JNJ-20788560等δ-阿片激动剂来缓解炎症性痛觉过敏。