School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, United Kingdom (A.E.C., R.H., G.H., E.K.); Faculty of Pharmacy, Gomal University, Khyber Pakhtunkhwa, Pakistan (J.A.); PharmInVivo Ltd., Szentagothai Research Centre, Centre for Neuroscience and Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary (E.B., V.T., Z.H.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (J.P., C.B.); and PharmNovo AB, Kungshamn, Sweden (I.S., B.v.M., D.K.).
School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, United Kingdom (A.E.C., R.H., G.H., E.K.); Faculty of Pharmacy, Gomal University, Khyber Pakhtunkhwa, Pakistan (J.A.); PharmInVivo Ltd., Szentagothai Research Centre, Centre for Neuroscience and Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary (E.B., V.T., Z.H.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (J.P., C.B.); and PharmNovo AB, Kungshamn, Sweden (I.S., B.v.M., D.K.)
J Pharmacol Exp Ther. 2020 Feb;372(2):224-236. doi: 10.1124/jpet.119.258640. Epub 2019 Oct 8.
Agonists at the opioid receptor are known to be potent antihyperalgesics in chronic pain models and effective in models of anxiety and depression. However, some opioid agonists have proconvulsant properties while tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the opioid receptor differentially engage signaling and regulatory pathways with significant effects on behavioral outcomes. As such, interest is now growing in the development of biased agonists as a potential means to target specific signaling pathways and potentially improve the therapeutic profile of opioid agonists. Here, we report on PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide), a novel G protein-biased and selective opioid agonist. In cell-based assays, PN6047 fully engages G protein signaling but is a partial agonist in both the arrestin recruitment and internalization assays. PN6047 is effective in rodent models of chronic pain but shows no detectable analgesic tolerance following prolonged treatment. In addition, PN6047 exhibited antidepressant-like activity in the forced swim test, and importantly, the drug had no effect on chemically induced seizures. PN6047 did not exhibit reward-like properties in the conditioned place preference test or induce respiratory depression. Thus, opioid ligands with limited arrestin signaling such as PN6047 may be therapeutically beneficial in the treatment of chronic pain states. SIGNIFICANCE STATEMENT: PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide) is a selective, G protein-biased opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment, and PN6047 does not display proconvulsant activity or other opioid-mediated adverse effects. Our data suggest that opioid ligands with limited arrestin signaling will be beneficial in the treatment of chronic pain.
阿片受体激动剂已知在慢性疼痛模型中具有强效的抗痛觉过敏作用，并在焦虑和抑郁模型中有效。然而，一些阿片受体激动剂具有致惊厥作用，同时也可能产生治疗效果的耐受性。先前的证据表明，作用于阿片受体的不同激动剂以不同的方式参与信号转导和调节途径，对行为结果有显著影响。因此，人们现在对开发偏向激动剂作为靶向特定信号通路的潜在手段产生了兴趣，这可能会改善阿片受体激动剂的治疗谱。在这里，我们报告了 PN6047（3-[[4-(二甲基氨基甲酰基)苯基]-[1-(噻唑-5-基甲基)-4-哌啶亚基甲基]苯甲酰胺），一种新型的 G 蛋白偏向性和选择性阿片受体激动剂。在基于细胞的测定中，PN6047完全参与 G 蛋白信号转导，但在 arrestin 募集和内化测定中均为部分激动剂。PN6047在慢性疼痛的啮齿动物模型中有效，但在长期治疗后没有检测到可察觉的镇痛耐受性。此外，PN6047在强迫游泳试验中表现出抗抑郁样活性，重要的是，该药物对化学诱导的癫痫发作没有影响。PN6047在条件性位置偏好试验中没有表现出奖赏样特性，也不会引起呼吸抑制。因此，像 PN6047 这样 arrestin 信号有限的阿片受体配体在治疗慢性疼痛状态方面可能具有治疗益处。
PN6047（3-[[4-(二甲基氨基甲酰基)苯基]-[1-(噻唑-5-基甲基)-4-哌啶亚基甲基]苯甲酰胺）是一种选择性、G 蛋白偏向性阿片受体激动剂，在慢性疼痛的临床前模型中有效。经过长期治疗，没有观察到镇痛耐受性，PN6047 没有表现出致惊厥作用或其他阿片类药物介导的不良反应。我们的数据表明，arrestin 信号有限的阿片受体配体将有益于慢性疼痛的治疗。
