The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability
| Autor: | Chen-ling Pan, Zehui Gong, Shou-Pu Yi, Peilan Zhou, Jie Yu, Yu-lei Li, Ying-fei Wang, Kwen-Jen Chang, Guanlin Wang, Ruibin Su, Gang Yu, Qinghong Kong, Cui Benqiang, Yue-hai Shen, Li-li Wang |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Agonist medicine.drug_class Molecular Conformation Receptors Opioid mu Pain CHO Cells Thiophenes Pharmacology Piperazines Structure-Activity Relationship 03 medical and health sciences Cricetulus 0302 clinical medicine Opioid receptor Receptors Opioid delta medicine Animals Humans Potency Pharmacology (medical) Rats Wistar Respiratory system Receptor ED50 Pain Measurement EC50 Dose-Response Relationship Drug business.industry Receptors Opioid kappa General Medicine Rats Analgesics Opioid 030104 developmental biology Opioid Original Article Analgesia Respiratory Insufficiency business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Acta Pharmacologica Sinica. 38:977-989 |
| ISSN: | 1745-7254 1671-4083 |
| DOI: | 10.1038/aps.2017.14 |
| Popis: | 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 DPI-125 and attempted to elucidate the relationship between the δ-, μ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing δ-, μ- or κ-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED50 (pCO2 increase)/ED50 (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for δ-, μ- and κ-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. DPI-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. DPI-125 has similar potencies for μ- and κ-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional μ-agonist analgesics. These findings suggest that the development of δ>μ∼κ opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink