JNJ-20788560 [9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic Acid Diethylamide], a Selective Delta Opioid Receptor Agonist, Is a Potent and Efficacious Antihyperalgesic Agent That Does Not Produce Respiratory Depression, Pharmacologic Tolerance, or Physical Dependence
JNJ-20788560 [9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic Acid Diethylamide], a Selective Delta Opioid Receptor Agonist, Is a Potent and Efficacious Antihyperalgesic Agent That Does Not Produce Respiratory Depression, Pharmacologic Tolerance, or Physical Dependence
复制标题
DOI：
10.1124/jpet.108.146969
复制
发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Flores, Christopher M.
中科院分区：
文献类型：
--
作者：
Codd, Ellen E.;Carson, John R.;Flores, Christopher M.
μ-阿片类镇痛剂是治疗多种来源的急性和慢性疼痛的主要药物，但是它们的副作用，例如便秘、呼吸抑制和滥用倾向，对患者产生不利影响。最近证实的增量调节和δ-阿片受体（DOR）的膜靶向炎症和随之而来的增强治疗效果的δ-阿片受体激动剂已经活跃的δ-阿片类镇痛剂的搜索。JNJ-20788560[9-（8-氮杂双环-[3.2.1]辛-3-亚基）-9H-咕吨-3-羧酸二乙基酰胺]对DOR的亲和力为2.0 nM（大鼠脑皮质结合试验），纳曲吲哚敏感性DOR效价为5.6 nM（5 '-O-（3-[（35）S]硫代）三磷酸盐试验）。该化合物的效力为7.6 mg/kg p.o.在大鼠酵母聚糖辐射热试验中，13.5 mg/kg p.o.在大鼠完全弗氏佐剂RH试验中，但在未发炎的辐射热试验中几乎没有活性。在有限的研究中，未观察到对该化合物的抗痛觉过敏或抗伤害感受作用的耐受性。与布洛芬不同，JNJ-20788560不会引起胃肠道（GI）糜烂。尽管吗啡在所有试验剂量下均降低GI蠕动，并在最高剂量下达到几乎完全效应，但JNJ-20788560在最低剂量下未延迟转运，在最高给药剂量下仅降低11%。与吗啡不同，JNJ-20788560未表现出呼吸抑制（血气分析），阿片类（mu或delta）拮抗剂给药未诱发戒断体征。再加上先前发表的阿芬太尼训练的灵长类动物缺乏化合物的自我给药行为，这些发现强烈建议使用μ阿片类激动剂（如JNJ-20788560）缓解炎性痛觉过敏。
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 upregulation 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 mu-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.