The opioid receptor triple agonist DP1-125 produces analgesia with less respiratory depression and reduced abuse liability  

作　　者：Shou-pu YI Qing-hong KONG Yu-lei LI Chen-ling PAN Jie YU Ben-qiang CUI Ying-fei WANG Guan-lin WANG Pei-lan ZHOU Li-li WANG Ze-hui GONG Rui-bin SU Yue-hai SHEN Gang YU Kwen-jen CHANG 

机构地区：[1]Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China [2]State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China [3]Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China [4]State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China

出　　处：《Acta Pharmacologica Sinica》2017年第7期977-989,共13页中国药理学报（英文版）

摘　　要：Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DP1-125 and attempted to elucidate the relationship between the 6-, p- and K-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds （DP1-125, DPI-3290, DPI-130, KUST202 and KUST13T02） were selected for this study. PKA fluorescence redistribution assays in CliO cells individually expressing 6-, p- or K-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of EDso （pC02 increase）/EDso （antinociception）. The abuse liability of DP1-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DP1-125 for 6-, μ- and K-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DP1-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC50 potencies for the μ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DP1-125 has similar potencies for μ- and K-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DP1-125 is safer and less addictive than traditional μ-agonist analgesics. These findings suggest that the development of δ〉μ-K opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DP1-125 and attempted to elucidate the relationship between the 6-, p- and K-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds （DP1-125, DPI-3290, DPI-130, KUST202 and KUST13T02） were selected for this study. PKA fluorescence redistribution assays in CliO cells individually expressing 6-, p- or K-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of EDso （pC02 increase）/EDso （antinociception）. The abuse liability of DP1-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DP1-125 for 6-, μ- and K-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DP1-125 exhibited a high respiratory safety profile, clearly related to its high δ-receptor potency. The ratio of the EC50 potencies for the μ- and δ-receptors was found to be positively correlated with the respiratory safety ratio. DP1-125 has similar potencies for μ- and K-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DP1-125 is safer and less addictive than traditional μ-agonist analgesics. These findings suggest that the development of δ〉μ-K opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.

关 键 词：opioid receptor mixed agonist DP1-125 ANALGESIA respiratory depression ADDICTION 

分 类 号：TQ463[化学工程—制药化工] Q593.2[生物学—生物化学]