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The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability
- Source :
- Acta Pharmacologica Sinica. 38:977-989
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 17457254 and 16714083
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Acta Pharmacologica Sinica
- Accession number :
- edsair.doi.dedup.....29204556c609cca8c89b0c7f01381cb8